EP3871673A1 - Nouveau composé d'indazole ou sel de celui-ci - Google Patents

Nouveau composé d'indazole ou sel de celui-ci Download PDF

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EP3871673A1
EP3871673A1 EP19874827.9A EP19874827A EP3871673A1 EP 3871673 A1 EP3871673 A1 EP 3871673A1 EP 19874827 A EP19874827 A EP 19874827A EP 3871673 A1 EP3871673 A1 EP 3871673A1
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Prior art keywords
methyl
tert
chloro
substituted
butyl
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EP19874827.9A
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EP3871673A4 (fr
EP3871673B1 (fr
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Toshihiro Sakamoto
Hideki Kazuno
Tetsuya Sugimoto
Hitomi KONDO
Tomohiro Yamamoto
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Taiho Pharmaceutical Co Ltd
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Taiho Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present application claims priority to Japanese Patent Application No. 2018-202226 filed on October 26, 2018 and Japanese Patent Application No. 2019-075118 filed on April 10, 2019 , which are incorporated herein by reference in their entirety.
  • the present invention relates to an indazole compound having inhibitory activity against KRAS G12C mutation or a salt thereof, and relates to a pharmaceutical composition comprising this as an active ingredient.
  • RAS which is a small monomeric GTP-binding protein having a molecular weight of about 21 kDa, acts as a molecular on/off switch.
  • RAS can bind to GTP by binding to proteins of a guanine nucleotide exchange factor (GEF) (e.g., SOS1), which forces the release of a bound nucleotide, and releasing GDP.
  • GEF guanine nucleotide exchange factor
  • SOS1 guanine nucleotide exchange factor
  • RAS binds to GTP, it becomes activated (turned on) and recruits and activates proteins necessary for the propagation of other receptors' signals, such as c-Raf and PI 3-kinase.
  • RAS also possesses enzymatic activity with which it cleaves the terminal phosphate of the nucleotide and converts it to GDP. The rate of conversion is usually slow, but can be dramatically sped up by a protein of the GTPase-
  • the mainly known members of the RAS subfamily include HRAS, KRAS, and NRAS.
  • mutations of KRAS are observed in many malignant tumors: 95% of pancreatic cancers, 45% of colorectal cancers, and 35% of lung cancers.
  • the mutations often occur in the glycine residue at position 12; in pulmonary adenocarcinoma, in particular, the mutation in the glycine residue at position 12 occurs in about 90% of the whole.
  • the most often occurring mutation (44%) has been reported to be a mutation into cysteine (Non-patent Literature (NPL) 1).
  • ARS-853 binds to the cysteine of the G12C mutant of inactive KRAS (GDP), thus preventing conversion of inactive KRAS (GDP) to active KRAS (GTP), inhibiting downstream signaling, and inducing apoptosis in cancer cells with KRAS G12C mutation (Patent Literature (PTL) 1 and NPL 2). It has also been reported that ARS-1620 with a quinazoline backbone exerts antitumor action in tumor-bearing mice expressing KRAS G12C mutation by improving metabolic stability of ARS-853 mice (PTL 2 and NPL 3).
  • An object of the present invention is to provide a novel compound or a salt thereof that binds to the mutant cysteine of KRAS and inhibits downstream signaling, and to provide a pharmaceutical composition comprising this.
  • the present inventors conducted extensive research to solve the above problems, and consequently found that the group of compounds represented by the following formula (I), containing indazole and heteroaryl, strongly binds to the cysteine of KRAS G12C mutant and inhibits functions of KRAS.
  • the present invention has thus been accomplished.
  • the present invention provides the following (1) to (43).
  • An indazole compound represented by Formula (I) or a salt thereof impairs the KRAS function in KRAS G12C mutation-positive cancer cells, thereby showing antitumor action; therefore, an indazole compound represented by Formula (I) or a salt thereof can be used as an anti-cancer agent.
  • the compound represented by Formula (I) above of the present invention contains indazole and a heteroaryl group in its basic structure, and is a novel compound that is nowhere disclosed in any of the literature cited above.
  • CA-CB used in the description of a group indicates that the group has A to B number of carbon atoms.
  • C1-C6 alkyl refers to alkyl having 1 to 6 carbon atoms
  • C6-C14 aromatic hydrocarbon oxy refers to oxy to which C6-C14 aromatic hydrocarbon is bonded.
  • A- to B-membered indicates that the number of atoms (number of ring members) that constitute a ring is A to B. More specifically, "4- to 10-membered saturated heterocyclic group” refers to a saturated heterocyclic group containing 4 to 10 ring members.
  • C denotes a carbon atom
  • N denotes a nitrogen atom
  • S denotes a sulfur atom
  • O denotes an oxygen atom
  • H denotes a hydrogen atom.
  • a double line denotes a double bond
  • a double line one line of which is a dotted line, denotes a single bond or a double bond.
  • examples of the "substituent" include hydrogen, halogen, cyano, nitro, amino, hydroxy, oxo, carbonyl, carboxy, carbamoyl, alkyl, haloalkyl, hydroxyalkyl, cyanoalkyl, cycloalkyl, cycloalkenyl, cycloalkyl-alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkoxy-alkyl, cycloalkoxy, cycloalkyl-alkoxy, cycloalkyl-haloalkyl, alkylthio, cycloalkyl-alkylthio, mono- or dialkylamino, alkylaminoalkyl, cycloalkyl-alkylamino, aromatic hydrocarbon, aralkyl, aralkyloxy, acyl, alkylcarbonyl, arylcarbonyl, acyl
  • halogen examples include chlorine, bromine, fluorine, and iodine, with chlorine, fluorine, and bromine being preferable, and chlorine and fluorine being more preferable.
  • alkyl refers to a linear or branched saturated hydrocarbon group.
  • examples include C1-C10 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, hexyl, and heptyl.
  • alkyl is preferably C1-C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl, and more preferably methyl, ethyl, or tert-butyl.
  • haloalkyl refers to alkyl mentioned above having at least one halogen atom (preferably having 1 to 10, and more preferably 1 to 3 halogen atoms).
  • Examples include C1-C6 haloalkyl, such as fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1,1,1-trifluoroethyl, 1-fluoro-n-propyl, 1,1,1-trifluoro-n-propyl, perfluoro-n-propyl, and perfluoroisopropyl, with trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, and 1,1,1-trifluoroethyl being preferable.
  • hydroxyalkyl refers to alkyl mentioned above having at least one hydroxy group (preferably having 1 to 10, and more preferably 1 to 2 hydroxy groups).
  • examples include C1-C6 hydroxyalkyl, such as hydroxymethyl, hydroxyethyl, 1-hydroxypropyl, and 2-hydroxybutyl.
  • cyanoalkyl refers to alky mentioned above having at least one cyano group (preferably having 1 to 10, and more preferably 1 to 2 cyano groups). Examples include C1-C6 cyanoalkyl, such as cyanomethyl, cyanoethyl, 1-cyanopropyl, and 2-cyanobutyl.
  • cycloalkyl refers to monocyclic, bridged cyclic, or polycyclic saturated hydrocarbon.
  • examples include C3-C10 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclodecyl, with cyclopropyl, cyclobutyl, and cyclopentyl being preferable, and cyclobutyl and cyclopentyl being particularly preferable.
  • cycloalkenyl refers to monocyclic, bridged cyclic, or polycyclic unsaturated hydrocarbon containing at least one carbon-carbon double bond (e.g., one to two carbon-carbon double bonds, and preferably one carbon-carbon double bond).
  • Examples include C4-C10 cycloalkenyl, such as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclodecenyl, with cyclobutenyl, cyclopentenyl, and cyclohexenyl being preferable, and cyclobutenyl and cyclopentenyl being particularly preferable.
  • cycloalkyl-alkyl refers to alkyl mentioned above having at least one cycloalkyl group.
  • examples include C3-C10 cycloalkyl-C1-C4 alkyl, such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylisopropyl, cyclohexyl 1-methyl-4-isopropyl, and cycloheptylmethyl, with cyclohexylmethyl being preferable.
  • the "unsaturated hydrocarbon” refers to linear or branched unsaturated hydrocarbon containing at least one carbon-carbon double bond or triple bond.
  • examples include C2-C10 unsaturated hydrocarbon, such as vinyl, allyl, methylvinyl, 1-propenyl, butenyl, pentenyl, hexenyl, ethynyl, and 2-propynyl, with C2-6 linear or branched hydrocarbon containing at least one carbon-carbon double bond or triple bond being preferable, vinyl, allyl, and 1-propenyl being more preferable, and vinyl being most preferable.
  • alkenyl refers to a linear or branched unsaturated hydrocarbon group containing at least one double bound (e.g., one to two double bonds, and preferably one double bond).
  • Examples include C2-C10 alkenyl, such as vinyl, allyl, 1-propenyl, 2-methyl-2-propenyl, isopropenyl, 1-, 2-, or 3-butenyl, 2-, 3- or 4-pentenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, and 5-hexenyl, with C2-C6 alkenyl, such as vinyl, allyl, 1-propenyl, and 2-methyl-2-propenyl being preferable, and vinyl being most preferable.
  • alkynyl refers to linear or branched unsaturated hydrocarbon containing at least one triple bond (e.g., one or two triple bonds, and preferably one triple bond).
  • examples include C2-C10 alkynyl, such as ethynyl, 1- or 2-propynyl, 1-, 2-, or 3-butynyl, and 1-methyl-2-propynyl, with C2-C6 alkynyl, such as ethynyl and 2-propynyl, being preferable, and 2-propynyl being most preferable.
  • alkoxy refers to oxy having alkyl mentioned above.
  • examples include C1-C6 alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, and hexyloxy, with methoxy and ethoxy being preferable, and methoxy being more preferable.
  • haloalkoxy refers to alkoxy mentioned above having at least one halogen atom (preferably having 1 to 13, and more preferably 1 to 3 halogen atoms).
  • examples include C1-C6 haloalkoxy, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, fluoroethoxy, 1,1-difluoroethoxy, 1,1,1-trifluoroethoxy, monofluoro-n-propoxy, perfluoro-n-propoxy, and perfluoro-isopropoxy, with fluoroethoxy, difluoromethoxy, and trifluoromethoxy being preferable.
  • alkoxy-alkyl refers to alkyl mentioned above having at least one alkoxy group mentioned above.
  • examples include C1-C4 alkoxy-C1-C10 alkyl, such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl, methoxy-n-, methoxypentyl, methoxyhexyl, methoxyheptyl, propoxyethyl, and butoxyethyl, with C1-C2 alkoxy-C1-C3 alkyl, such as methoxymethyl, ethoxymethyl, methoxyethyl, and ethoxyethyl being preferable, and methoxymethyl and methoxyethyl being more preferable.
  • cycloalkoxy refers to oxy having cycloalkyl mentioned above.
  • examples include C3-C10 cycloalkoxy, such as cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and cycloheptyloxy, with cyclobutoxy, cyclopentyloxy, and cyclohexyloxy being preferable.
  • cycloalkyl-alkoxy refers to alkoxy mentioned above having at least one cycloalkyl group mentioned above.
  • examples include C3-C10 cycloalkyl-C1-C4 alkoxy, such as cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, and cycloheptylmethoxy, with cyclohexylmethoxy being preferable.
  • cycloalkyl-haloalkyl refers to haloalkyl mentioned above having at least one cycloalkyl group mentioned above.
  • examples include C3-C10 cycloalkyl-C1-C4 haloalkyl, such as cyclopropylfluoromethyl, cyclobutylfluoromethyl, cyclopentylfluoromethyl, cyclohexylfluoromethyl, and cycloheptylfluoromethyl, with cyclohexylfluoromethyl being preferable.
  • alkylthio refers to thioxy having alkyl mentioned above.
  • Examples include C1-C6 alkylthio, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, n-pentylthio, isopentylthio, and hexylthio, with methylthio and ethylthio being preferable.
  • cycloalkyl-alkylthio refers to alkylthio mentioned above having at least one cycloalkyl group mentioned above.
  • examples include C3-C7 cycloalkyl-C1-C4 alkylthio, such as cyclopropylmethylthio, cyclobutylmethylthio, cyclopentylmethylthio, cyclohexylmethylthio, and cycloheptylmethylthio, with cyclohexylmethylthio being preferable.
  • alkylamino refers to amino having one or two alkyl groups mentioned above. Specific examples include C1-C6 alkylamino, such as methylamino, ethylamino, dimethylamino, diethylamino, and ethylmethylamino, with methylamino, dimethylamino, and methylethylamino being preferable.
  • the "monoalkylamino” refers to amino having one alkyl group mentioned above.
  • Examples include C1-C6 monoalkylamino, such as methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino, n-pentylamino, isopentylamino, and hexylamino, with methylamino being preferable.
  • dialkylamino refers to amino having two alkyl groups mentioned above.
  • examples include C2-C12 dialkylamino, such as dimethylamino, diethylamino, di(n-propyl)amino, diisopropylamino, di(n-butyl)amino, diisobutylamino, di(tert-butyl)amino, di(n-pentyl)amino, diisopentylamino, dihexylamino, methylethylamino, and methylisopropylamino, with dimethylamino being preferable.
  • alkylaminoalkyl refers to alkyl mentioned above having at least one alkylamino group mentioned above.
  • examples include C1-C6 alkylamino-C1-C6 alkyl, such as methylaminomethyl, methylaminoethyl, ethylaminomethyl, and ethylaminopropyl, with dimethylaminomethyl and dimethylaminoethyl being preferable.
  • cycloalkyl-alkylamino refers to alkylamino mentioned above having cycloalkyl mentioned above in which cycloalkyl is attached to the alkyl moiety of alkylamino.
  • examples include C3-C7 cycloalkyl-C1-C4 alkylamino, such as cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino, and cycloheptylmethylamino, with cyclobutylmethylamino and cyclohexylmethylamino being preferable.
  • aromatic hydrocarbon refers to monocyclic or polycyclic aromatic hydrocarbon as being an unsaturated bond-containing ring substituent containing carbon and hydrogen, the monocyclic or polycyclic aromatic hydrocarbon containing 4e+2 number of electrons (e is an integer of 1 or more) in the cyclic ⁇ electron system.
  • examples include phenyl, naphthyl, tetrahydronaphthyl, anthracenyl, and the like, with phenyl being preferable.
  • aralkyl refers to alkyl mentioned above substituted with aromatic hydrocarbon mentioned above.
  • examples include C7-C16 aralkyl, such as benzyl, phenylethyl, phenylpropyl, naphthylmethyl, and naphthylethyl, with benzyl being preferable.
  • aralkyloxy refers to oxy having aralkyl mentioned above.
  • examples include C7-C20 aralkyloxy, such as benzyloxy, phenethyloxy, naphthylmethyloxy, and fluorenylmethyloxy, with benzyloxy being preferable.
  • acyl refers to carbonyl having alkyl mentioned above or aryl.
  • Examples include substituted C1-C16 carbonyl, such as methylcarbonyl, ethylcarbonyl, and phenylcarbonyl, with methylcarbonyl and ethylcarbonyl being preferable.
  • alkylcarbonyl refers to carbonyl having alkyl mentioned above, and is also included in the synonym "acyl.”
  • Examples include C1-C6 alkylcarbonyl, such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, and hexylcarbonyl, with methylcarbonyl being preferable.
  • C1-C6 alkylcarbonyl refers to (C1-C6 alkyl)carbonyl.
  • arylcarbonyl refers to carbonyl having aromatic hydrocarbon mentioned above, and is also included in the synonym “acyl.”
  • Examples include (C6-C20 aryl)carbonyl, such as phenylcarbonyl, naphthylcarbonyl, fluorenylcarbonyl, anthrylcarbonyl, biphenylylcarbonyl, tetrahydronaphthylcarbonyl, chromanylcarbonyl, 2,3-dihydro-1,4-dioxanaphthalenylcarbonyl, indanylcarbonyl, and phenanthrylcarbonyl.
  • acyloxy refers to oxy having C1-C16 acyl mentioned above.
  • the acyloxy is preferably oxy binding to substituted C1-C16 acyl, such as acetoxy, ethylacyloxy, and phenylacyloxy, and more preferably acetoxy, tert-butylcarbonyloxy, or phenylcarbonyloxy.
  • alkylcarbonyloxy refers to oxy having alkylcarbonyl mentioned above, and is included in the synonym “acyloxy.”
  • Examples include (C1-C6 alkyl)carbonyloxy, such as methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, isobutylcarbonyloxy, tert-butylcarbonyloxy, n-pentylcarbonyloxy, isopentylcarbonyloxy, and hexylcarbonyloxy, with acetoxy and tert-butylcarbonyloxy being preferable.
  • arylcarbonyloxy refers to oxy having arylcarbonyl mentioned above, and is included in the synonym “acyloxy.”
  • Examples include (C6-C14 aryl)carbonyloxy, such as phenylcarbonyloxy, naphthylcarbonyloxy, fluorenylcarbonyloxy, anthrylcarbonyloxy, biphenylylcarbonyloxy, tetrahydronaphthylcarbonyloxy, chromanylcarbonyloxy, 2,3-dihydro-1,4-dioxanaphthalenylcarbonyloxy, indanylcarbonyloxy, and phenanthrylcarbonyloxy, with phenylcarbonyloxy being preferable.
  • alkoxycarbonyl refers to carbonyl having alkoxy mentioned above.
  • examples include (C1-C6 alkoxy)carbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, and hexyloxycarbonyl, with methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl being preferable, and tert-butoxycarbonyl being more preferable.
  • aralkyloxycarbonyl refers to carbonyl having aralkyloxy mentioned above.
  • examples include (C6-C20 aralkyl)oxycarbonyl, such as benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethyloxycarbonyl, and fluorenylmethyloxycarbonyl, with benzyloxycarbonyl being preferable.
  • saturated heterocyclic group refers to a monocyclic or polycyclic saturated heterocyclic group containing at least one heteroatom (preferably having 1 to 5, and more preferably 1 to 3 heteroatoms) selected from nitrogen, oxygen, and sulfur.
  • Examples include aziridinyl, azetidinyl, imidazolidinyl, morpholino, pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, thiazolidinyl, thianyl, oxazolidinyl, morpholyl, and the like, with azetidinyl, pyrrolidinyl, and piperidinyl being preferable, and azetidinyl and pyrrolidinyl being more preferable.
  • the "unsaturated heterocyclic group” refers to a monocyclic or polycyclic, completely or partially unsaturated heterocyclic group containing at least one heteroatom (preferably containing 1 to 5, and more preferably 1 to 3 heteroatoms) selected from nitrogen, oxygen, and sulfur.
  • Examples include imidazolyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indazolyl, triazolopyridyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, furanyl, benzofuranyl, purinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalyl, methylenedioxyphenyl, ethylenedioxyphenyl, dihydrobenzofuranyl, and the like, with imidazolyl, pyrazolyl, thiazo
  • saturated heterocyclic oxy refers to oxy having a saturated heterocyclic group mentioned above.
  • saturated heterocyclic group examples include morpholinyloxy, 1-pyrrolidinyloxy, piperidinooxy, piperazinyloxy, 4-methyl-1-piperazinyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, tetrahydrothiophenyloxy, thiazolidinyloxy, oxazolidinyloxy, and the like, with azetidinyloxy and pyrrolidinyloxy being preferable.
  • X represents nitrogen or CH, and preferably CH.
  • R 1 represents hydrogen, halogen, cyano, nitro, amino, hydroxy, carboxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, C6-C10 aromatic hydrocarbon, a 4- to 10-membered saturated heterocyclic group, or a 5- to 10-membered unsaturated heterocyclic group.
  • halogen represented by R 1 is preferably fluorine, chlorine, or bromine, and more preferably chlorine.
  • C1-C6 alkyl in the "substituted or unsubstituted C1-C6 alkyl” represented by R 1 is preferably methyl, ethyl, n-propyl, or isopropyl (C1-C3 alkyl), more preferably methyl or ethyl, and particularly preferably methyl.
  • the substituent in the "substituted or unsubstituted C1-C6 alkyl" represented by R 1 may be, for example, the substituents mentioned above, and is preferably, halogen, cyano, or hydroxy, and more preferably fluorine, chlorine, cyano, or hydroxy.
  • the "substituted or unsubstituted C1-C6 alkyl" represented by R 1 is preferably C1-C6 alkyl, more preferably methyl, ethyl, or tert-butyl, more preferably methyl or ethyl, and particularly preferably methyl.
  • C2-C6 alkenyl in the "substituted or unsubstituted C2-C6 alkenyl” represented by R 1 is preferably vinyl, 1-propenyl, allyl, or isopropenyl, and more preferably 1-propenyl.
  • the substituent in the "substituted or unsubstituted C2-C6 alkenyl" represented by R 1 may be, for example, the substituents mentioned above, and is preferably halogen or hydroxy, and more preferably chlorine or fluorine.
  • the "substituted or unsubstituted C2-C6 alkenyl" represented by R 1 is preferably 1-propenyl or 2-methyl-2-propenyl.
  • C2-C6 alkynyl in the "substituted or unsubstituted C2-C6 alkynyl” represented by R 1 is preferably ethynyl or 1-propynyl.
  • the substituent in the "substituted or unsubstituted C2-C6 alkynyl" represented by R 1 may be, for example, the substituents mentioned above, and is preferably halogen or hydroxy, and more preferably fluorine or chlorine.
  • the "substituted or unsubstituted C2-C6 alkynyl" represented by R 1 is preferably C2-C6 alkynyl, and more preferably ethynyl or 1-propynyl.
  • C3-C10 cycloalkyl in the "substituted or unsubstituted C3-C10 cycloalkyl” represented by R 1 is preferably cyclobutyl, cyclopentyl, or cyclohexyl.
  • the substituent in the "substituted or unsubstituted C3-C10 cycloalkyl" represented by R 1 may be, for example, the substituents mentioned above, and is preferably halogen or C1-C6 alkyl, and more preferably methyl, ethyl, n-propyl, fluorine, or chlorine.
  • the "substituted or unsubstituted C3-C10 cycloalkyl" represented by R 1 is preferably C3-C10 cycloalkyl, and more preferably cyclobutyl, cyclopentyl, or cyclohexyl.
  • the "C6-C10 aromatic hydrocarbon” represented by R 1 is preferably phenyl.
  • the "4- to 10-membered saturated heterocyclic group" represented by R 1 is preferably a monocyclic or bicyclic 4- to 10-membered saturated heterocyclic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, more preferably a monocyclic 4- to 7-membered saturated heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and more preferably aziridinyl, pyrrolidinyl, or piperidinyl.
  • the "5- to 10-membered unsaturated heterocyclic group" represented by R 1 is preferably a monocyclic or bicyclic 5- to 10-membered unsaturated heterocyclic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, more preferably a monocyclic 5- to 7-membered unsaturated heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and more preferably pyridyl.
  • R 1 is preferably hydrogen, halogen, or a substituted or unsubstituted C1-C6 alkyl.
  • R 1 is more preferably hydrogen, halogen, or C1-C6 alkyl.
  • R 1 is more preferably halogen or C1-C6 alkyl.
  • R 1 is more preferably halogen or methyl.
  • R 1 is more preferably chlorine or methyl.
  • R 1 is most preferably chlorine.
  • R 2 represents hydrogen, cyano, nitro, amino, hydroxy, carboxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, C6-C10 aromatic hydrocarbon, a 4- to 10-membered saturated heterocyclic group, or a 5- to 10-membered unsaturated heterocyclic group.
  • the "C1-C6 alkyl" in the "substituted or unsubstituted C1-C6 alkyl” represented by R 2 is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, or n-pentyl, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl, more preferably methyl, ethyl, or tert-butyl, and most preferably tert-butyl.
  • the substituent in the "substituted or unsubstituted C1-C6 alkyl" represented by R 2 may be, for example, the substituents mentioned above, and is preferably halogen, cyano, hydroxy, or C3-C7 cycloalkyl, and more preferably fluorine, chlorine, cyclopropyl, or cyclobutyl.
  • the "substituted or unsubstituted C1-C6 alkyl" represented by R 2 is preferably C1-C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, and n-pentyl, more preferably methyl, ethyl, isopropyl, and tert-butyl, still more preferably isopropyl or tert-butyl, and most preferably tert-butyl.
  • C1-C6 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, and n-pentyl, more preferably methyl, ethyl, isopropyl, and tert-butyl, still
  • C2-C6 alkenyl in the "substituted or unsubstituted C2-C6 alkenyl” represented by R 2 is preferably vinyl, 1-propenyl, allyl, or isopropenyl, and more preferably vinyl or isopropenyl.
  • the substituent in the "substituted or unsubstituted C2-C6 alkenyl" represented by R 2 may be, for example, the substituents mentioned above, and is preferably halogen, cyano, or hydroxy, more preferably chlorine or fluorine, and more preferably fluorine.
  • the "substituted or unsubstituted C2-C6 alkenyl" represented by R 2 is preferably C2-C6 alkenyl that may contain halogen, more preferably vinyl, 1-propenyl, 2-methyl-2-propenyl, or 1-(trifluoromethyl)vinyl, and more preferably vinyl or 1-(trifluoromethyl)vinyl.
  • C2-C6 alkynyl in the "substituted or unsubstituted C2-C6 alkynyl” represented by R 2 is preferably ethynyl or 1-propynyl.
  • the substituent in the "substituted or unsubstituted C2-C6 alkynyl" represented by R 2 may be, for example, the substituents mentioned above, and is preferably halogen or hydroxy, more preferably fluorine or chlorine, and still more preferably fluorine.
  • the "substituted or unsubstituted C2-C6 alkynyl" represented by R 2 is preferably ethynyl or 1-propynyl.
  • C3-C10 cycloalkyl in the "substituted or unsubstituted C3-C10 cycloalkyl” represented by R 2 is preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and more preferably cyclopropyl.
  • the substituent in the "substituted or unsubstituted C3-C10 cycloalkyl" represented by R 2 may be, for example, the substituents mentioned above, and is preferably halogen, C1-C6 alkyl, or C1-C6 haloalkyl, more preferably fluorine, chlorine, methyl, ethyl, n-propyl, fluoromethyl, difluoromethyl, or trifluoromethyl, and still more preferably fluorine, methyl, ethyl, or trifluoromethyl.
  • the "substituted or unsubstituted C3-C10 cycloalkyl" represented by R 2 is preferably C3-C10 cycloalkyl that may contain C1-C6 haloalkyl, and more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or 1-(trifluoromethyl)cyclopropyl.
  • the "C6-C10 aromatic hydrocarbon” represented by R 2 is preferably phenyl.
  • the "4- to 10-membered saturated heterocyclic group" represented by R 2 is preferably a monocyclic or bicyclic 4- to 10-membered saturated heterocyclic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, and more preferably a monocyclic 4- to 7-membered saturated heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and more preferably aziridinyl, pyrrolidinyl, piperidinyl, or tetrahydropyranyl.
  • the "5- to 10-membered unsaturated heterocyclic group" represented by R 2 is preferably a monocyclic or bicyclic 5- to 10-membered unsaturated heterocyclic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, more preferably a monocyclic 5- to 7-membered unsaturated heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and more preferably pyridyl.
  • R 2 is preferably substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, or substituted or unsubstituted C3-C10 cycloalkyl.
  • R 2 is more preferably C1-C6 alkyl, C2-C6 alkenyl that may contain halogen, or C3-C10 cycloalkyl that may contain C1-C6 haloalkyl.
  • R 2 is more preferably C1-C6 alkyl, vinyl, 1-(trifluoromethyl)vinyl, or 1-(trifluoromethyl)cyclopropyl.
  • R 2 is more preferably C1-C6 alkyl.
  • R 2 is more preferably C3-C6 alkyl.
  • R 2 is most preferably tert-butyl.
  • Ras are identical or different, and each represents a hydrogen atom, a deuterium atom, or C1-C6 alkyl.
  • the "C1-C6 alkyl” represented by Ra is preferably methyl or ethyl, and most preferably methyl.
  • Ra is preferably a hydrogen atom, a deuterium atom, or methyl, and most preferably a hydrogen atom.
  • L 1 repesents -NH-C(Ra) 2 -.
  • L 1 preferably represents -NH-C(Ra) 2 , wherein one of the two Ras is a hydrogen atom while the other is a hydrogen atom, a deuterium atom, or methyl, and most preferably -NH-CH 2 -.
  • ring A represents a substituted or unsubstituted 5-membered unsaturated heterocyclic group.
  • Ring A typically represents a substituted or unsubstituted 5-membered unsaturated heterocyclic group containing two double bonds in the ring.
  • A1, A2, and A3 are identical or different, and represent substituted or unsubstituted carbon, substituted or unsubstituted nitrogen, sulfur, or oxygen
  • one of A1, A2, and A3 represents substituted or unsubstituted nitrogen or sulfur
  • two of the rest of A1, A2, and A3 are identical or different, and represent substituted or unsubstituted carbon, substituted or unsubstituted nitrogen, sulfur, or oxygen.
  • Ring A is preferably a substituted or unsubstituted group in which two hydrogen atoms are removed from imidazole, pyrazole, thiazole, or oxazol, more preferably a substituted or unsubstituted group in which two hydrogen atoms are removed from imidazole, pyrazole, or thiazole, and most preferably a substituted or unsubstituted group in which two hydrogen atoms are removed from imidazole.
  • the "5-membered unsaturated heterocyclic group" represented by ring A is preferably a group in which two hydrogen atoms are removed from imidazole, pyrazole, thiazole, or oxazol, more preferably a substituted or unsubstituted group in which two hydrogen atoms are removed from imidazole, pyrazole, or thiazole, and most preferably a group in which two hydrogen atoms are removed from imidazole.
  • the substituent in the "substituted or unsubstituted 5-membered unsaturated heterocyclic group" represented by ring A may be, for example, the substituents mentioned above, and is preferably hydrogen, halogen, cyano, nitro, amino, hydroxy, carboxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C4-C10 cycloalkenyl, substituted or unsubstituted C6-C10 aromatic hydrocarbon, a substituted or unsubstituted 4- to 10- membered saturated heterocyclic group, or a substituted or unsubstituted 5- to 10-membered unsaturated heterocyclic group.
  • halogen included in the substituents of ring A is preferably fluorine or chlorine.
  • C1-C6 alkyl in the "substituted or unsubstituted C1-C6 alkyl” included in the substituents of ring A is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, or n-pentyl, and more preferably methyl or ethyl.
  • the substituent in the "substituted or unsubstituted C1-C6 alkyl" included in the substituents of ring A may be, for example, the substituents mentioned above, and is preferably halogen, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C6-C10 aromatic hydrocarbon, or a substituted or unsubstituted 4- to 10-membered saturated heterocyclic group, more preferably halogen, C1-C6 alkoxy, C1-C6 alkylamino, C3-C10 cycloalkyl that may contain C1-C6 alkoxy, C6-C10 aromatic hydrocarbon, or a 4- to 10-membered saturated heterocyclic group that may contain C1-C6 alkyl, and more preferably halogen, C1
  • the "substituted or unsubstituted C1-C6 alkyl" included in the substituents of ring A is preferably C1-C6 alkyl substituted or unsubstituted with at least one substituent selected from the group consisting of halogen, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C6-C10 aromatic hydrocarbon, and a substituted or unsubstituted 4- to 10-membered saturated heterocyclic group, more preferably C1-C6 alkyl substituted or unsubstituted with at least one substituent selected from the group consisting of halogen, C1-C6 alkoxy, C1-C6 alkylamino, C3-C10 cycloalkyl that may contain C1-C6 alkoxy, C6-
  • C2-C6 alkenyl in the "substituted or unsubstituted C2-C6 alkenyl” included in the substituents of ring A is preferably vinyl or allyl.
  • the substituent in the "substituted or unsubstituted C2-C6 alkenyl" included in the substituents of ring A may be, for example, the substituents mentioned above, and is preferably halogen, and more preferably fluorine or chlorine.
  • the "substituted or unsubstituted C2-C6 alkenyl" included in the substituents of ring A is preferably vinyl or allyl.
  • C2-C6 alkynyl in the "substituted or unsubstituted C2-C6 alkynyl” included in the substituents of ring A is preferably ethynyl or 1-propynyl.
  • the substituent in the "substituted or unsubstituted C2-C6 alkynyl" included in the substituents of ring A may be, for example, the substituents mentioned above, and is preferably halogen, and more preferably fluorine or chlorine.
  • the "substituted or unsubstituted C2-C6 alkynyl" included in the substituents of ring A is preferably ethynyl or 1-propynyl.
  • C3-C10 cycloalkyl in the "substituted or unsubstituted C3-C10 cycloalkyl” included in the substituents of ring A include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclodecyl, and the like, with C3-C7 cycloalkyl being preferable, and cyclopropyl, cyclopentyl, and cyclohexyl being more preferable.
  • the substituent in the "substituted or unsubstituted C3-C10 cycloalkyl" included in the substituents of ring A may be, for example, the substituents mentioned above, and is preferably hydroxy, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted C1-C6 alkoxy, more preferably hydroxy, C1-C6 alkyl, or C1-C6 alkoxy, and more preferably hydroxy, methyl, isopropyl, or methoxy.
  • the "substituted or unsubstituted C3-C10 cycloalkyl" included in the substituents of ring A is preferably C3-C10 cycloalkyl substituted or unsubstituted with a substituent selected from the group consisting of hydroxy, substituted or unsubstituted C1-C6 alkyl, and substituted or unsubstituted C1-C6 alkoxy, more preferably C3-C10 cycloalkyl substituted or unsubstituted with a substituent selected from the group consisting of hydroxy, C1-C6 alkyl, and C1-C6 alkoxy, more preferably C3-C7 cycloalkyl substituted or unsubstituted with a substituent selected from the group consisting of hydroxy, C1-C6 alkyl, and C1-C6 alkoxy, and more preferably cyclopropyl, cyclopentyl, cyclohexyl, 3,4-
  • C4-C10 cycloalkenyl in the "substituted or unsubstituted C4-C10 cycloalkenyl” included in the substituents of ring A include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclodecenyl, and the like, with C4-C7 cycloalkenyl being preferable, and cyclopentenyl being more preferable.
  • the substituent in the "substituted or unsubstituted C4-C10 cycloalkenyl" included in the substituents of ring A may be, for example, the substituents mentioned above, and is preferably halogen, and more preferably fluorine or chlorine.
  • the "substituted or unsubstituted C4-C10 cycloalkenyl" included in the substituents of ring A is preferably C4-C10 cycloalkenyl, more preferably C4-C7 cycloalkenyl, and more preferably cyclopentenyl.
  • C6-C10 aromatic hydrocarbon in the "substituted or unsubstituted C6-C10 aromatic hydrocarbon” included in the substituents of ring A is preferably phenyl, naphthyl, or tetrahydronaphthyl, and more preferably phenyl.
  • the substituent in the "substituted or unsubstituted C6-C10 aromatic hydrocarbon" included in the substituents of ring A may be, for example, the substituents mentioned above, and is preferably halogen, and more preferably fluorine or chlorine.
  • the "substituted or unsubstituted C6-C10 aromatic hydrocarbon” included in the substituents of ring A is preferably C6-C10 aromatic hydrocarbon, and more preferably phenyl.
  • the "4- to 10-membered saturated heterocyclic group" in the "substituted or unsubstituted 4- to 10-membered saturated heterocyclic group” included in the substituents of ring A is preferably a monocyclic or bicyclic 4- to 10-membered saturated heterocyclic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur, more preferably a monocyclic 4- to 7-membered saturated heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, and more preferably azetidinyl, pyrrolidinyl, or piperidinyl.
  • the "substituent" in the "substituted or unsubstituted 4- to 10-membered saturated heterocyclic group” included in the substituents of ring A may be, for example, the substituents mentioned above, and is preferably substituted or unsubstituted C1-C6 alkyl, C1-C6 alkenyl, (C1-C6 alkyl)carbonyl, (C1-C6 alkoxy)carbonyl, C3-C10 cycloalkyl, C6-C10 aromatic hydrocarbon, a 4- to 10-membered saturated heterocyclic group, or a 5- to 10-membered unsaturated heterocyclic group, more preferably C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy-C1-C6 alkyl, C7-C16 aralkyl, C1-C6 alkenyl, (C1-C6 alkyl)carbonyl, (C1-C6 al
  • the "substituted or unsubstituted 4- to 10-membered saturated heterocyclic group" included in the substituents of ring A is preferably N-tert-butoxycarbonylazetidinyl, N-isopropylazetidinyl, N-acetylazetidinyl, N-methylpyrrolidinyl, N-ethylpyrrolidinyl, N-acetylpyrrolidinyl, N-isopropylpyrrolidinyl, N-pyridinepyrrolidinyl, N-2-methoxyethyl-pyrrolidinyl, N-cyclopropylpyrrolidinyl, N-oxetanylpyrrolidinyl, N-benzylpyrrolidinyl, N-carboxylateazetidinyl, N-difluoroethyl-pyrrolidinyl, N-prop-2-enyl-pyrrolidinyl, 1-(
  • the "5- to 10-membered unsaturated heterocyclic group" included in the substituents of ring A is preferably pyridinyl.
  • the substituent in the "substituted or unsubstituted 5-to 10-membered unsaturated heterocyclic group" included in the substituent of ring A may be, for example, the substituents mentioned above, and is preferably halogen, hydroxy, or C1-C6 alkyl, and more preferably methyl, ethyl, hydroxy, fluorine, or chlorine.
  • the "substituted or unsubstituted 5- to 10-membered unsaturated heterocyclic group" in the “substituted or unsubstituted 5- to 10-membered unsaturated heterocyclic group” included in the substituents of ring A is preferably a 5- to 10-membered unsaturated heterocyclic group, and more preferably pyridinyl or N-methylpyridinyl.
  • L 2 represents wherein represent a 4- to 8-membered saturated heterocyclic group that may contain 1 or 2 heteroatoms selected from sulfur and oxygen, and that contains at least one, and preferably 1 or 2, nitrogen atoms, and
  • L 2 preferably represents a 4- to 8-membered saturated heterocyclic group that does not contain sulfur or oxygen, and contains at least one nitrogen atom (preferably one or two nitrogen atoms), and more preferably, azetidinyl, pyrrolidinyl, or piperidinyl.
  • L 2 preferably represents a 4- to 8-membered saturated heterocyclic group that does not contain sulfur or oxygen, and contains at least one nitrogen atom (preferably one or two nitrogen atoms), and more preferably azetidinyl, pyrrolidinyl, or piperidinyl.
  • L 2 preferably represents a 4- to 8-membered saturated heterocyclic group that does not contain sulfur or oxygen, and contains at least two (preferably two or three) nitrogen atoms, and more preferably 1,3-diazetidinyl, imidazolidinyl, or piperazinyl.
  • the "C1-C6 alkyl" represented by R 3 is preferably methyl or ethyl, and more preferably methyl.
  • the "halogen" represented by R 4 is preferably fluorine.
  • the "C1-C6 alkyl" represented by R 4 is preferably methyl or ethyl.
  • the "C2-C6 alkenyl” represented by R 4 is preferably vinyl or allyl.
  • the "C2-C6 alkynyl” represented by R 4 is preferably ethynyl.
  • the "C1-C6 alkoxy" represented by R 4 is preferably methoxy.
  • the "C1-C6 haloalkyl" represented by R 4 is preferably fluoromethyl.
  • the "C1-C6 cyanoalkyl" represented by R 4 is preferably cyanomethyl.
  • C1-C6 alkylamino-C1-C6 alkyl represented by R 4 is preferably N,N-dimethylaminomethyl.
  • C1-C6 alkoxy-C1-C6 alkyl represented by R 4 is preferably methoxymethyl or methoxyethyl, and more preferably methoxymethyl.
  • the "C1-C6 hydroxyalkyl" represented by R 4 is preferably hydroxymethyl or 2-hydroxyethyl, and more preferably hydroxymethyl.
  • R 4 s When two R 4 s are attached to the same carbon atom, and these two R 4 s each represent C1-C6 alkyl, these two R 4 s, taken together with the carbon atom to which these groups are attached, may form a ring.
  • Such a ring has a structure in which, for example, two hydrogen atoms that attach to the same carbon are removed from C3-C6 (preferably C3-C4, and more preferably C3) cycloalkane.
  • n 0, 1, 2, or 3. n is preferably 0, 1, or 2, more preferably 0 or 1, and most preferably 0.
  • L 2 above represent a 4- to 6-membered saturated heterocyclic group containing 1 or 2 nitrogen atoms
  • R 3 represents hydrogen or methyl
  • R 4 represents halogen, cyano, cyanomethyl, hydroxy, C1-C2 alkyl, methoxy, C1-C2 haloalkyl, C1-C2 hydroxyalkyl, dimethylaminomethyl, methoxymethyl, or ethoxymethyl.
  • these two R 4 s when two R 4 s are attached to the same carbon atom, and these two R 4 s each represent C1-C2 alkyl, these two R 4 s, taken together with the carbon atom to which these groups are attached, may form a structure in which two hydrogen atoms that attach to the same carbon are removed from C3-C5 (preferably C3) cycloalkane.
  • L 2 represents wherein
  • R 5 represents substituted or unsubstituted C2-C6 alkenyl or substituted or unsubstituted C2-C6 alkynyl.
  • the compound or a salt thereof according to the present invention has structural features as represented by Formula (I) above; in particular, due to the above structure of R 5 , the compound or a salt thereof according to the present invention can specifically bind to the cysteine residue of the G12C mutant of KRAS.
  • C2-C6 alkenyl in the "substituted or unsubstituted C2-C6 alkenyl” represented by R 5 is preferably vinyl, 1-propenyl, allyl, or isopropenyl.
  • the "substituent" in the "substituted or unsubstituted C2-C6 alkenyl” represented by R 5 may be, for example, the substituents mentioned above, and is preferably halogen, C1-C6 alkylamino, C1-C6 alkoxy, or a 4- to 10-membered saturated heterocyclic group, and more preferably chlorine, methoxymethyl, dimethylamino, or piperidinyl.
  • the "substituted or unsubstituted C2-C6 alkenyl" represented by R 5 is preferably vinyl, 1-propenyl, 1-chlorovinyl, 2-chlorovinyl, 3-(dimethylamino)prop-1-en-1-yl, 3-(piperidin-1-yl)prop-1-en-1-yl, or 3-(methoxy)prop-1-en-1-yl.
  • C2-C6 alkynyl in the "substituted or unsubstituted C2-C6 alkynyl” represented by R 5 is preferably ethynyl, 1-propynyl, or 2-propynyl.
  • the substituent in the "substituted or unsubstituted C2-C6 alkynyl" represented by R 5 may be, for example, the substituents mentioned above, and is preferably halogen, C1-C6 alkyl, or C1-C6 alkoxy, and more preferably fluorine, chlorine, methyl, or methoxy.
  • the "substituted or unsubstituted C2-C6 alkynyl" represented by R 5 is preferably ethynyl.
  • R 5 is preferably substituted or unsubstituted C2-C6 alkenyl, more preferably substituted or unsubstituted C2-C3 alkenyl, and most preferably vinyl.
  • R 5 is preferably substituted or unsubstituted C2-C6 alkenyl or substituted or unsubstituted C2-C6 alkynyl (the substituent is selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkoxy, and 4- to 10-membered saturated heterocyclic group), more preferably substituted or unsubstituted C2-C6 alkenyl (the substituent is selected from the group consisting of halogen, C1-C6 alkylamino, C1-C6 alkoxy, and 4- to 10-membered saturated heterocyclic group) or substituted or unsubstituted C2-C6 alkynyl (the substituent is selected from halogen, C1-C6 alkyl, and C1-C6 alkoxy), more preferably substituted or unsubstituted C2-C3 alkenyl (the substituent is selected from the group consisting of chlorine, methoxy
  • the alkyl when ring A is substituted with alkyl, the alkyl is preferably not substituted with C6-C10 aromatic hydrocarbon, a 4- to 10-membered saturated heterocyclic group, or a 5- to 10-membered unsaturated heterocyclic group.
  • the substituent is at least one member selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, hydroxy, carboxy, C1-C6 alkyl that may have Rb, C2-C6 alkenyl that may have Rb, C2-C6 alkynyl that may have Rb, C3-C10 cycloalkyl that may have Rc, C3-C10 cycloalkenyl that may have Rc, C6-C10 aromatic hydrocarbon that may have Rc, a 4- to 10-membered saturated heterocyclic group that may have Rc, and a 4-to 10-membered unsaturated heterocyclic group that may have Rc.
  • Rb represents halogen, cyano, nitro, amino, hydroxy, carboxy, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl, substituted or unsubstituted C6-C10 aromatic hydrocarbon, or a substituted or unsubstituted 4- to 10-membered saturated heterocyclic group
  • Rc represents halogen, cyano, nitro, amino, hydroxy, carboxy, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 alkylcarbonyl, C1-C6 alkoxy-C1-C6 alkyl, C7-C20 aralkyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, C6-C10 aromatic hydro
  • Rb is preferably halogen, C1-C6 alkoxy, C1-C6 alkylamino, C3-C10 cycloalkyl, substituted or unsubstituted C6-C10 aromatic hydrocarbon, or a substituted or unsubstituted 4- to 10-membered saturated heterocyclic group.
  • Rb is more preferably halogen, C1-C3 alkoxy, C1-C3 alkylamino, C3-C6 cycloalkyl, substituted or unsubstituted phenyl, or a substituted or unsubstituted 4- to 5-membered saturated heterocyclic group.
  • Rb is more preferably chlorine, fluorine, methoxy, cyclopentyl, phenyl, 2,4-dimethoxyphenyl, dimethylamino, or N-isopropyl-pyrrolidinyl.
  • Rb is more preferably chlorine, methyl, ethyl, cyano, difluoromethyl, trifluoromethyl, or 2,4-dimethoxyphenyl.
  • Rc is preferably halogen, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 alkylamino, C1-C6 alkylcarbonyl, C1-C6 alkoxy-C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxycarbonyl, C7-C20 aralkyl, a 4- to 10- membered saturated heterocyclic group, or a 5- to 10-membered unsaturated heterocyclic group.
  • Rc is more preferably halogen, hydroxy, C1-C3 alkyl, C2-C3 alkenyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 alkylamino, C1-C3 alkylcarbonyl, C1-C3 alkoxy C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxycarbonyl, benzyl, a 4- to 6-membered saturated heterocyclic group, or a 5- to 6-membered unsaturated heterocyclic group.
  • Rc is still more preferably chlorine, fluorine, hydroxy, methyl, ethyl, isopropyl, acetyl, methoxy, vinyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, cyclopropyl, oxetanyl, benzyl, tert-butoxycarbonyl, methoxyethyl, or pyridinyl.
  • A1 preferably represents substituted carbon or substituted nitrogen, and the substituent is preferably hydrogen, cyano, halogen, C1-C6 alkyl that may have Rb, C2-C6 alkenyl that may have Rb, C3-C10 cycloalkyl that may have Rc, C4-C10 cycloalkenyl that may have Rc, a 4- to 10- membered saturated heterocyclic group that may have Rc, or a 4- to 10- membered unsaturated heterocyclic group that may have Rc.
  • A1 more preferably represents substituted nitrogen, and the substituent is hydrogen, halogen, C1-C6 alkyl (substituted or unsubstituted with a substituent selected from the group consisting of halogen, C1-C6 alkoxy, C1-C6 alkylamino, C3-C10 cycloalkyl, substituted or unsubstituted C6-C10 aromatic hydrocarbon, and a substituted or unsubstituted, 4- to 10-membered saturated heterocyclic group), C3-C10 cycloalkyl (substituted or unsubstituted with a substituent selected from the group consisting of hydroxy, C1-C6 alkyl, and C1-C6 alkoxy), C3-C10 cycloalkenyl, a 4- to 10- membered saturated heterocyclic group (substituted or unsubstituted with a substituent selected from the group consisting of C1-C6 alkyl, C1-
  • A1 more preferably represents substituted nitrogen, and the substituent is hydrogen, halogen, C1-C6 alkyl (substituted or unsubstituted with a substituent selected from the group consisting of halogen, C1-C3 alkoxy, C1-C3 alkylamino, C3-C6 cycloalkyl, substituted or unsubstituted phenyl, and a substituted or unsubstituted 4- to 5-membered saturated heterocyclic group), C3-C6 cycloalkyl (substituted or unsubstituted with a substituent selected from the group consisting of hydroxy, C1-C3 alkyl, and C1-C3 alkoxy), C3-C6 cycloalkenyl, a 4- to 5-membered saturated heterocyclic group (substituted or unsubstituted with a substituent selected from the group consisting of C1-C3 alkyl, C1-C3 halo
  • A1 still more preferably represents substituted nitrogen, and the substituent is hydrogen, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl, 3,4-dihydroxycyclopentyl, cyclohexyl, 2-isopropyl-5-methylcyclohexyl, 4-methoxycyclohexyl, cyclopentenyl, N-tert-butoxycarbonylaziridinyl, N-isopropylaziridinyl, N-methylcarbonylaziridinyl, N-methylpyrrolidinyl, N-ethylpyrrolidinyl, N-isopropylpyrrolidinyl, N-(2,2-difluoroethyl)pyrrolidinyl, N-methylcarbonylpyrrolidinyl, N-methoxyethylpyr
  • A1 still more preferably represents substituted nitrogen, and the substituent is hydrogen, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, 4-methoxycyclohexyl, N-isopropylaziridinyl, N-methylpyrrolidinyl, N-isopropylpyrrolidinyl, N-(2,2-difluoroethyl)pyrrolidinyl, N-(2,2-difluoroethyl)piperidinyl, tetrahydrofuranyl, or tetrahydropyranyl.
  • A2 preferably represents sulfur or substituted nitrogen, and the substituent is hydrogen, halogen, cyano, nitro, amino, hydroxy, carboxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, or substituted or unsubstituted C2-C6 alkynyl.
  • A2 still more preferably represents substituted nitrogen, and the substituent is hydrogen, halogen, cyano, hydroxy, or C1-C6 alkyl.
  • A2 still more preferably represents substituted nitrogen, and the substituent is hydrogen, methyl, or ethyl.
  • the substituent of A2 is most preferably nitrogen that is substituted with hydrogen.
  • A3 preferably represens substituted carbon or substituted nitrogen, and the substituent is hydrogen, halogen, cyano, nitro, amino, hydroxy, carboxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, or substituted or unsubstituted C2-C6 alkynyl.
  • A3 more preferably represens substituted carbon or substituted nitrogen, and the substituent is hydrogen, halogen, cyano, nitro, amino, hydroxy, carboxy, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, or C2-C6 alkynyl.
  • A3 still more preferably represents substituted carbon, and the substituent is hydrogen, halogen, cyano, C1-C6 alkyl, or C1-C6 haloalkyl.
  • A3 most preferably represents substituted carbon, and the substituent is methyl, ethyl, difluoromethyl, chlorine, fluorine, or cyano.
  • a preferable combination of A1, A2, and A3 is a combination of A1 being substituted nitrogen, A2 being nitrogen, and A3 being substituted carbon; a combination of A1 being nitrogen, A2 being sulfur, and A3 being substituted carbon; a combination of A1 being substituted carbon, A2 being nitrogen, and A3 being substituted nitrogen; or a combination of A1 being sulfur, A2 being nitrogen, and A3 being substituted carbon.
  • a more preferable combination of A1, A2, and A3 is a combination of A1 being substituted nitrogen, A2 being nitrogen, and A3 being substituted carbon; or a combination of A1 being nitrogen, A2 being sulfur, and A3 being substituted carbon.
  • a most preferable combination of A1, A2, and A3 is a combination of A1 being substituted nitrogen, A2 being nitrogen, and A3 being substituted carbon.
  • the compound or a salt thereof of the present invention is preferably a compound represented by Formula (I) or a salt thereof, wherein X represents nitrogen or CH, R 1 represents hydrogen, halogen, cyano, nitro, amino, hydroxy, carboxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, C6-C10 aromatic hydrocarbon, a 4- to 10-membered saturated heterocyclic group, or a 5- to 10-membered unsaturated heterocyclic group, L 1 represents -NH-C(Ra) 2 -, wherein Ras are identical or different, and each represents a hydrogen atom, a deuterium atom, or C1-C6 alkyl, ring A represents a substituted or unsubstituted, 5-membered unsaturated heterocycl
  • the compound or a salt thereof of the present invention is more preferably a compound represented by Formula (I) or a salt thereof, wherein X represents N or CH, R 1 represents halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, or substituted or unsubstituted C3-C10 cycloalkyl, L 1 represents -NH-C(Ra) 2 -, and one of the two Ras is a hydrogen atom while the other is a hydrogen atom, a deuterium atom, or methyl, wherein Ras are identical or different, and each represents a hydrogen atom, a deuterium atom, or methyl, ring A is a combination of A1, A2, and A3, wherein A1 is substituted nitrogen, A2 is nitrogen, and A3 is substituted carbon; A1 is substituted nitrogen, A2 is sulfur, and A3 is substituted carbon; A1 is substituted carbon, A2 is nitrogen, and A
  • the compound or a salt thereof of the present invention is still more preferably a compound represented by Formula (I) or a salt thereof, wherein X represents CH, R 1 represents halogen, substituted or unsubstituted C1-C3 alkyl, 1-propenyl, 2-methyl-2-propenyl, or 1-methylcyclopropyl, L 1 represents -NH-C(Ra) 2 -, and one of the two Ras is a hydrogen atom while the other is a hydrogen atom, a deuterium atom, or methyl, wherein Ras are identical or different, and each represents a hydrogen atom, a deuterium atom, or methyl, ring A is a combination of A1, A2, and A3, wherein A1 is substituted nitrogen, A2 is nitrogen, and A3 is substituted carbon; or A1 is substituted nitrogen, A2 is sulfur, and A3 is substituted carbon; the substituent of A1 is hydrogen, halogen, C1-C6 alkyl (substituted or unsub
  • the compound or a salt thereof of the present invention is still more preferably a compound represented by Formula (I) or a salt thereof, wherein X represents CH, R 1 represents chlorine or substituted C1-C3 alkyl, L 1 represents -NH-CH 2 -, wherein Ras are identical or different, and each represents a hydrogen atom, a deuterium atom, or methyl, ring A is a combination of A1, A2, and A3, wherein A1 is substituted nitrogen, A2 is nitrogen, and A3 is substituted carbon; or A1 is nitrogen, A2 is sulfur, and A3 is substituted carbon, the substituent of A1 is hydrogen, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclopentyl, 3,4-dihydroxycyclopentyl, cyclohexyl, 2-isopropyl-5-methylcyclohexyl
  • the compound or a salt thereof of the present invention is most preferably a compound represented by Formula (I) or a salt thereof, wherein X represents CH, R 1 represents chlorine or tert-butyl, L 1 represents -NH-CH 2 -, wherein Ras are identical or different, and each represents a hydrogen atom, a deuterium atom, or methyl, ring A is a combination of A1, A2, and A3, wherein A1 is substituted nitrogen, A2 is nitrogen, and A3 is substituted carbon, the substituent of A1 is hydrogen, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, 4-methoxycyclohexyl, N-isopropylaziridinyl, N-methylpyrrolidinyl, N-isopropylpyrrolidinyl, N-(2,2-difluoroethyl)pyrrol
  • the compound or a salt thereof of the present invention is preferably a compound represented by Formula (I) or a salt thereof, wherein X represents nitrogen or CH, R 1 represents hydrogen, halogen, cyano, nitro, amino, hydroxy, carboxy, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, C6-C10 aromatic hydrocarbon, a 4- to 10-membered saturated heterocyclic group, or a 5- to 10-membered unsaturated heterocyclic group, L 1 represents -NH-C(Ra) 2 -, wherein Ras are identical or different, and each represents a hydrogen atom, a deuterium atom, or C1-C6 alkyl, ring A represents a substituted or unsubstituted, 5-membered unsaturated heterocycl
  • the compound or a salt thereof of the present invention is more preferably a compound represented by Formula (I) or a salt thereof, wherein X represents CH, R 1 represents halogen, substituted or unsubstituted C1-C3 alkyl, 1-propenyl, 2-methyl2-propenyl, or 1-methylcyclopropyl, L 1 represents -NH-C(Ra) 2 -, wherein Ras are identical or different, and each represents a hydrogen atom, a deuterium atoms, or methyl, ring A represents a substituted or unsubstituted group in which two hydrogen atoms are removed from imidazole, pyrazole, or thiazole, L 2 represents wherein
  • the compound or a salt thereof of the present invention is still more preferably a compound represented by Formula (I) or a salt thereof, wherein X represents CH, R 1 represents chlorine or substituted C1-C3 alkyl, L 1 represents -NH-C(Ra) 2 -, wherein Ras are identical or different, and each represents a hydrogen atom, a deuterium atom, or methyl, ring A represents a substituted or unsubstituted group in which two hydrogen atoms are removed from imidazole, pyrazole, or thiazole, L 2 represents wherein
  • the compound or a salt thereof of the present invention is most preferably a compound represented by Formula (I) or a salt thereof, wherein X represents CH, R 1 represents chlorine or tert-butyl, L 1 represents -NH-C(Ra) 2 -, wherein Ras are identical or different, and each represents a hydrogen atom, a deuterium atom, or methyl, ring A represents a substituted or unsubstituted group in which two hydrogen atoms are removed from imidazole, L 2 represents wherein
  • Examples of specific compounds of the present invention include, but are not limited to, the compounds produced in the Examples below.
  • Examples of preferable compounds of the present invention include the following:
  • the compound represented by Formula (I) of the present invention can be produced, for example, through the following production methods or the methods described in the Examples. However, the production methods for the compound represented by Formula (I) of the present invention are not limited to these reaction examples.
  • the reaction product obtained in each step can be subjected to the subsequent step after, or without, isolation and purification by known separation and purification methods, such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, and chromatography.
  • a protecting group that can be easily converted to the functional group can be introduced if it is effective in each step, or so as to change the order of the steps.
  • the protecting group used here may be the protecting groups etc. used in the method disclosed in the document " Protective Groups in Organic Synthesis," 5th edition, Greene and Wuts, John Wiley & Sons Inc., 2014 .
  • the protecting group may be appropriately selected according to the reaction conditions of each step. After introducing a protecting group and performing reaction, the protecting group is optionally removed to thus yield a desired compound.
  • step A compound (III) is used in an amount of 0.5 to 10 mol, and preferably 1 to 3 mol, per mol of compound (II).
  • Step A is performed in a solvent inactive to the reaction by adding a condensation agent suitable as an amidation reagent, and stirring under cooling or heating, preferably at -20°C to 80°C, usually for 1 minute to 1 week.
  • condensation agent used here examples include, but are not particularly limited to, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, benzotriazol-1-yloxy-tris-(dimethylamino)phosphonium hexafluorophosphate, benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate, bromotris-(dimethylamino)phosphonium hexafluorophosphate, diphenylphosphoryl azide, 1,1'-carbonyldiimidazole, and the like.
  • solvent used here examples include, but are not particularly limited to, toluene, methylene chloride, chloroform, THF, 1,4-dioxane, DMF, N,N-dimethylacetamide, NMP, 2-propanol, ethanol, methanol, water, and the like, and mixtures thereof. It is also possible to add additives, such as 1-hydroxybenzotriazole and a base, if necessary.
  • the base include, but are not particularly limited to, inorganic bases, such as sodium carbonate, potassium carbonate, and sodium hydrogen carbonate; organic bases, such as triethylamine, N,N-diisopropylethylamine, and 4-dimethylaminopyridine; and mixtures thereof.
  • step B known reaction methods for introducing a formyl group may be used. For example, the following methods are applicable:
  • A, L 2 , PG 1 , R a , R 1 , R 2 , and X are as defined above.
  • Step C is performed using compound (VI) in an amount of 0.5 to 10 mol, and preferably 0.5 to 2 mol, per mol of compound (V-1).
  • Step C is performed in a solvent suitable for the reaction by using a reducing agent and optionally adding additives.
  • the solvent include toluene, methylene chloride, chloroform, ethyl acetate, THF, 1,4-dioxane, N,N-dimethylformamide, N-methylpyrrolidone, DMSO, methanol, ethanol, 2-propanol, tert-butylalcohol, and the like, and mixed solvents thereof.
  • Examples of the reducing agent used here include, but are not particularly limited to, a metal hydride complex, etc. (e.g., 0.1 mol or a large excessive molar amount of sodium borohydride, sodium cyanoborohydride, or triacetoxyborohydride.)
  • Example of the additives used here include, but are not particularly limited to, acids, bases, and inorganic salts or organic salts. Examples include 0.01 mol or a large excessive molar amount of trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, potassium carbonate, sodium hydroxide, lithium hydroxide, sodium sulfate, magnesium sulfate, titanium isopropoxide, and the like.
  • X 1 represents a leaving group
  • A, L 2 , PG 1 , and R a are as defined above.
  • Step D can be performed by using N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, bromine, iodine, etc.
  • the solvent is not particularly limited as long as it does not affect the reaction.
  • the reaction may be performed in an appropriate solvent that does not affect the invention, such as acetonitrile, ethyl acetate, THF, methanol, ethanol, DMF, N,N-dimethylacetamide, NMP, chloroform, and carbon tetrachloride.
  • the reaction temperature is usually 0°C to 100°C, and preferably room temperature to reflux temperature.
  • the reaction time is usually 10 minutes to 3 days, and preferably 30 minutes to 24 hours.
  • the method for introducing a leaving group in step E is not particularly limited.
  • sulfonyl esterification may be performed under the conditions such that methanesulfonyl chloride, toluenesulfonyl chloride, etc. and an appropriate base are used.
  • halogenation may be performed under such conditions that a halogenating agent, such as carbon tetrachloride, carbon tetrabromide, or iodine, and triphenylphosphine etc. are used, or that a sulfonyl ester mentioned above is treated with lithium halide etc. and converted into a halogen group.
  • A, L 2 , PG 1 , R a , R 1 , R 2 , X, and X 1 are as defined above.
  • step F compound (VI) is used in an amount of 0.5 to 10 mol, and preferably 1 to 3 mol, per mol of compound (V-2).
  • solvents include toluene, methylene chloride, chloroform, THF, 1,4-dioxane, DMF, N-methylpyrrolidone, DMSO, methanol, ethanol, isopropanol, tert-butyl alcohol, and the like, and mixed solvents thereof.
  • Examples of the base used here include inorganic bases, such as sodium hydrogen carbonate, potassium carbonate, cesium carbonate, and potassium hydroxide; and organic bases, such as potassium-tert-butyrate, sodium-tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, triethylamine, and N,N-diisopropylethylamine.
  • inorganic bases such as sodium hydrogen carbonate, potassium carbonate, cesium carbonate, and potassium hydroxide
  • organic bases such as potassium-tert-butyrate, sodium-tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, triethylamine, and N,N-diisoprop
  • compound (VII) is subjected to deprotection reaction of step G to obtain compound (X), and the obtained compound is subjected to amidation reaction of step H to thus produce a compound represented by Formula (I).
  • PG 1 is hydrogen
  • compound (VII) is subjected to amidation reaction of step H to produce a compound represented by Formula (I).
  • the amine protecting group used here is not particularly limited. Examples include tert-butoxycarbonyl, benzyloxycarbonyl, and the like.
  • step G the following methods can be used, although it varies depending on the type of the protecting group: solvolysis using an acid or a base according to the method disclosed in the document " Protective Groups in Organic Synthesis," fifth edition, Green and Wuts, John Wiley & Sons Inc., 2014 , or a similar method, i.e., a method comprising reacting with 0.01 mol or a large excessive molar amount of an acid, preferably trifluoroacetic acid, formic acid, or hydrochloric acid, or an equimolar to large excessive molar amount of a base, preferably sodium hydroxide, lithium hydroxide, etc.; chemical reduction using a metal hydride complex etc.; or catalytic reduction using a palladium-carbon catalyst, Raney nickel catalyst, etc.
  • an acylating reagent is used in an amount of 0.5 to 10 mol, per mol of compound (X) obtained in the previous step, and the mixture is stirred in a solvent inactive to the reaction in the presence of a base under cooling to heating, preferably at -20°C to 80°C, usually for 3 days from the completion of the addition of the acylating reagent.
  • solvent used here examples include, but are not particularly limited to, ethers, such as THF, diethyl ether, 1,4-dioxane, and 1,2-dimethoxyethane; halogenated hydrocarbons, such as dichloromethane, 1,2-dichloroethane, and chloroform; alcohols, such as methanol and ethanol; aromatic hydrocarbons, such as benzene, toluene, and xylene; DMF, DMSO, ethyl acetate, acetonitrile, water, and mixtures thereof.
  • ethers such as THF, diethyl ether, 1,4-dioxane, and 1,2-dimethoxyethane
  • halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chloroform
  • alcohols such as methanol and ethanol
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • Examples of the base used here include inorganic bases, such as sodium carbonate, potassium carbonate, and sodium hydrogen carbonate; organic bases, such as triethylamine and N,N-diisopropylethylamine; and mixtures thereof.
  • Examples of the acylating reagent include acid halide compounds and acid anhydrides. Examples of acid halide compounds include acryloyl chloride and the like.
  • carboxylic acid is used in an amount of 0.5 to 10 mol, and preferably 1 to 3 mol, per mol of compound (X), and the mixture is stirred in a solvent inactive to the reaction in the presence of a condensation agent, and optionally in the presence of a base, under cooling to heating, preferably at -20°C to 80°C, usually for 1 minute to 3 days.
  • condensation agent examples include, but are not particularly limited to, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, benzotriazol-1-yloxy-tris-(dimethylamino)phosphonium hexafluorophosphate, benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate, bromotris-(dimethylamino)phosphonium hexafluorophosphate, diphenylphosphoric acid azide, 1,1'-carbonyldiimidazole, and the like.
  • solvent used here examples include, but are not particularly limited to, toluene, methylene chloride, chloroform, THF, 1,4-dioxane, DMF, N,N-dimethylacetamide, NMP, 2-propanol, ethanol, methanol, water, and mixtures thereof.
  • additives such as a base
  • bases include, but are not particularly limited to, inorganic bases, such as sodium carbonate, potassium carbonate, and sodium hydrogen carbonate; organic bases, such as triethylamine, N,N-diisopropylethylamine, and 4-dimethylaminopyridine; and mixtures thereof.
  • X 2 represents halogen
  • PG 2 represents an ester protecting group
  • A, R a , and X 1 are as defined above.
  • a known reaction is used to produce a compound represented by Formula (XII-1) or Formula (XII-2) from a commercially available aromatic ring ester or from an aromatic ring ester that can be synthesized by known methods.
  • A, L 2 , L 3 , PG 2 , R a , R 1 , R 2 , R 5 , X, and X 1 are as defined above.
  • step I reaction of carboxylic acid ester hydrolysis well known in the field of organic chemistry is applicable.
  • This hydrolysis reaction is not particularly limited, and may be performed, for example, by solvolysis using an acid or a base, i.e., a method comprising reacting with 0.01 mol or a large excessive molar amount of an acid, preferably trifluoroacetic acid, formic acid, hydrochloric acid, or the like, or an equimolar to large excessive molar amount of a base, preferably sodium hydroxide, lithium hydroxide, or the like.
  • an acid or a base i.e., a method comprising reacting with 0.01 mol or a large excessive molar amount of an acid, preferably trifluoroacetic acid, formic acid, hydrochloric acid, or the like, or an equimolar to large excessive molar amount of a base, preferably sodium hydroxide, lithium hydroxide, or the like.
  • X 3 represents a substituent that is convertible into cyano or the like. Examples include halogen, amine, ester, amide, carboxylic acid, and the like.
  • X 4 represents a substituent that is convertible into hydrazine or the like. Examples include a protector etc. for halogen, amine, and hydrazine.
  • R 1 , R 2 , and X are as defined above.
  • step J a method well known in the field of organic chemistry is used to introduce a cyano group.
  • a diazotization agent is used at -20°C to room temperature in an appropriate solvent to prepare a diazonium salt, and the obtained diazonium salt is added at -20 to 100°C to a solution of a base and a cyanating agent.
  • usable reaction solvents include acidic solvents, such as hydrochloric acid, acetic acid, trifluoroacetic acid, and sulfuric acid; alcohols, such as methanol and ethanol; water; and mixtures thereof.
  • Examples of the diazotization agent include sodium nitrite, isopentyl nitrite, and the like.
  • Examples of the base include sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, and the like.
  • Examples of the cyanating agent include sodium cyanide, potassium cyanide, copper cyanide, zinc cyanide, and the like, and mixtures thereof.
  • the reaction may also be performed at room temperature to 200°C using a cyanating agent in an appropriate solvent. In the reaction, a palladium catalyst etc. may be added as additives.
  • Examples of the cyanating agent include sodium cyanide, potassium cyanide, copper cyanide, zinc cyanide, and the like, and mixtures thereof.
  • the usable reaction solvent is not limited as long as it does not affect the reaction.
  • examples include ethers, such as THF and 1,4-dioxane; alcohols, such as methanol and ethanol; amides, such as DMF, N,N-dimethylacetamide, and N-methyl-2-pyrrolidone; hydrocarbons, such as toluene; acetonitrile; dimethylsulfoxide; water; and mixed solvents thereof.
  • step K for example, when X 4 in Formula (XVII) is halogen, hydrazine etc. may be reacted at 20 to 200°C in an appropriate solvent. It is also possible to subject hydrazine etc. protected by a protecting group to cross-coupling reaction using a palladium catalyst, and thereafter remove the hydrazine protecting group.
  • the reaction solvent usable here is not limited as long as it does not affect the reaction.
  • Examples include ethers, such as THF and 1,4-dioxane; alcohols, such as methanol and ethanol; amides, such as DMF, N,N-dimethylacetamide, and N-methyl-2-pyrrolidone; hydrocarbons, such as toluene; acetonitrile; dimethylsulfoxide; water; and mixed solvents thereof.
  • ethers such as THF and 1,4-dioxane
  • alcohols such as methanol and ethanol
  • amides such as DMF, N,N-dimethylacetamide, and N-methyl-2-pyrrolidone
  • hydrocarbons such as toluene
  • acetonitrile such as toluene
  • dimethylsulfoxide water
  • mixed solvents thereof such as toluene
  • Examples of the palladium catalyst usable here include palladium acetate, palladium chloride, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium, dichlorobisacetonitrile palladium, and tris(dibenzylideneacetone) dipalladium (0). It is appropriate to use the palladium catalyst in an amount of 0.001 to 1 mol, per mol of the compound represented by formula (XVII).
  • Examples include organic bases, such as potassium-tert-butyrate, sodium-tert-butyrate, sodium methoxide, sodium ethoxide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide; and inorganic bases, such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, sodium phosphate, and potassium phosphate. Although it varies depending on the reaction temperature, the reaction may be performed for 30 minutes to 24 hours.
  • the hydrazine protecting group may be removed, for example, by the method disclosed in the document " Protective Groups in Organic Synthesis,” fifth edition, Greene and Wuts, John Wiley & Sons Inc., 2014 , or a similar method, although it varies depending on the type of the protecting group used.
  • any of the isomers and mixtures thereof are included within the scope of the compound of the present invention unless otherwise specified.
  • the compound of the present invention has optical isomers, racemic mixtures and the optical isomers separated from a racemic mixture are also included within the scope of the compound of the present invention unless otherwise specified.
  • the compound or a salt thereof of the present invention may be in the form of amorphous or crystals. Single crystals and polymorphic mixtures are included within the scope of the compound or a salt thereof of the present invention. Such crystals can be produced by crystallization according to a crystallization method known in the art.
  • the compound or a salt thereof of the present invention may be a solvate (e.g., a hydrate) or a non-solvate. Any of such forms are included within the scope of the compound or a salt thereof of the present invention.
  • Compounds labeled with an isotope e.g., 2 H, 3 H, 13 C, 14 C, 35 S, 125 I
  • an isotope are also included within the scope of the compound or a salt thereof of the present invention.
  • the salts of the compound of the present invention refer to any pharmaceutically acceptable salts; examples include base addition salts and acid addition salts.
  • the compound or a salt thereof of the present invention also encompass prodrugs thereof.
  • a prodrug refers to a compound that can be converted to the compound or a salt thereof of the present invention through a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, i.e., a compound that can be converted to the compound or a salt thereof of the present invention by enzymatic oxidation, reduction, hydrolysis, or the like; or a compound that can be converted to the compound or a salt thereof of the present invention by hydrolysis or the like with gastric acid or the like.
  • the prodrug may be compounds that can be converted to the compound or a salt thereof of the present invention under physiological conditions, such as those described in Iyakuhin no Kaihatsu, "Development of Pharmaceuticals," Vol. 7, Molecular Design, published in 1990 by Hirokawa Shoten Co., pp. 163-198 .
  • a pharmaceutical carrier can be added, if required, thereby forming a suitable dosage form according to prevention and treatment purposes.
  • the dosage form include oral preparations, injections, suppositories, ointments, inhalations, patches, and the like.
  • Such dosage forms can be formed by methods conventionally known to a person skilled in the art.
  • various conventional organic or inorganic carrier materials used as preparation materials may be blended as an excipient, binder, disintegrant, lubricant, or colorant in solid preparations; or as a solvent, solubilizing agent, suspending agent, isotonizing agent, buffer, or soothing agent in liquid preparations.
  • pharmaceutical preparation additives such as antiseptics, antioxidants, colorants, sweeteners, and stabilizers, may also be used, if required.
  • Oral solid preparations are prepared as follows. After an excipient is added optionally with a binder, disintegrant, lubricant, colorant, taste-masking or flavoring agent, etc. to the compound or a salt thereof of the present invention, the resulting mixture is formulated into tablets, coated tablets, granules, powders, capsules, or the like by ordinary methods.
  • a pH regulator, a buffer, a stabilizer, an isotonizing agent, a local anesthetic, and the like may be added to the compound of the present invention; and the mixture may be formulated into a subcutaneous, intramuscular, or intravenous injection according to an ordinary method.
  • the amount of the compound of the present invention to be incorporated in each of such dosage unit forms depends on the condition of the patient to whom the compound is administered, the dosage form, etc. In general, for an oral agent, the amount of the compound is preferably about 0.05 to 1000 mg per dosage unit form. For an injection, the amount of the compound is preferably about 0.01 to 500 mg per dosage unit form, and for a suppository, the amount of the compound is preferably about 1 to 1000 mg per dosage unit form.
  • the daily dose of the medicine in such a dosage form varies depending on the condition, body weight, age, sex, etc. of the patient, and cannot be unconditionally determined.
  • the daily dose for an adult (body weight: 50 kg) of the compound of the present invention may be generally about 0.05 to 5000 mg, and preferably 0.1 to 1000 mg.
  • the compound or a salt thereof of the present invention has excellent KRAS inhibitory activity against KRAS G12C mutation-positive cancer cells, and also has excellent selectivity for wild-type KRAS normal cells. Therefore, the compound or a salt thereof of the present invention is useful as an antitumor agent against KRAS G12C mutation-positive cancer cells, and has the advantage of fewer side effects.
  • the compound or a salt thereof of the present invention inhibits the KRAS function and is useful as a pharmaceutical preparation for preventing and/or treating KRAS-associated signaling-related diseases.
  • an administration of the compound or a salt thereof of the present invention, in combinaion with an effective amount of one or more other antitumor agents can prevent and/or treat KRAS-associated signaling-related diseases (in particular, tumors).
  • KRAS is involved in various signaling transduction as RAS-associated signaling; KRAS mainly activates, but is not limited to, RAF, PI3K, RAL-GEF, and the like.
  • the diseases include diseases whose incidence can be reduced, and whose symptoms can be remitted, relieved, and/or completely cured by deleting, suppressing, and/or inhibiting their functions. Examples of such diseases include, but are not limited to, cancers, autoimmune diseases, macroglobulinemia, and the like.
  • tumors targeted in the present invention include, but are not particularly limited to, head and neck cancer, digestive organ cancer (esophageal cancer, stomach cancer, duodenal cancer, liver cancer, biliary cancer (e.g., gallbladder and bile duct cancer), pancreatic cancer, colorectal cancer (e.g., colon cancer, and rectal cancer), etc.), lung cancer (e.g., non-small-cell lung cancer, small-cell lung cancer, and mesothelioma), breast cancer, genital cancer (ovarian cancer, uterine cancer (e.g., cervical cancer and endometrial cancer), etc.), urological cancer (e.g., kidney cancer, bladder cancer, prostate cancer, and testicular tumor), hematopoietic tumor (e.g., leukemia, malignant lymphoma, and multiple myeloma), osteosarcoma, soft-tissue sarcoma, skin cancer, brain tumor, and the like.
  • lung cancer e.g.
  • the reagents used in the Examples are commercially available products unless indicated otherwise. Prepacked columns manufactured by Shoko Scientific Co., Ltd., or Biotage were used in silica gel column chromatography and basic silica gel column chromatography. An AL400 spectrometer (400 MHz; JEOL Ltd. (JEOL)) or Mercury 400 (400 MHz; Varian) spectrometer was used for NMR spectra. For a deuterated solvent containing tetramethylsilane, tetramethylsilane was used as the internal reference. In other cases, measurement was performed using an NMR solvent as the internal reference. All ⁇ values are indicated in ppm. Microwave reaction was performed using an Initiator (trademark) manufactured by Biotage.
  • Rhodium carbon (Rh 5%) (100 mg) was added to a solution of 6-chloro-5-vinyl-1H-indazole-3-amine (135 mg) obtained in Production Example 2 in THF (1.0 mL) and ethanol (1.0 mL) in a nitrogen atmosphere, and the reaction system was subjected to hydrogen replacement, followed by stirring for 5 days. The reaction system was then subjected to nitrogen replacement, and the reaction mixture was filtered. The solvent was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:ethanol), thereby obtaining the title compound (31 mg).
  • step 2 The procedure of Production Example 20 (step 2) was performed except that tert-butyl amine was used instead of cyclopropylamine used in Production Example 20 (step 2), thereby obtaining the title compound.
  • step 1 The procedure of Production Example 13 (step 1) was performed except that (S)-1-(tert-butoxycarbonyl)-3-pyrrolidinol was used instead of methanol used in Production Example 13 (step 1), thereby obtaining the title compound (10.61 g, >99%ee).
  • step 1 The procedure of Production Example 13 (step 1) was performed except that (R)-1-(tert-butoxycarbonyl)-3-pyrrolidinol was used instead of methanol used in Production Example 13 (step 1), thereby obtaining the title compound (659 mg, >99%ee).
  • Production Example 42 (step 1), N-bromosuccinimide was used instead of N-chlorosuccinimide. Thereafter, Production Example 42 (steps 2 and 3) was performed, and the synthesized ethyl 3-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-bromo-1-methyl-1H-pyrazole-5-carboxylate (0.23 g) was dissolved in 1,4-dioxane (1.0 mL).
  • Methyl boric acid (0.046 g), a potassium phosphate aqueous solution (2N, 0.10 mL), and a (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride dichloromethane adduct (0.004 g) were added thereto.
  • Trifluoroacetic acid (1.00 mL) was added to a solution of methyl (R)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-4-chloro-2-formyl-1H-imidazole-5-carboxylate (2.16 g) obtained in Production Example 25 and 5-(tert-butyl)-6-chloro-1H-indazole-3-amine (1.34 g) obtained in Production Example 1 in THF (30 mL), followed by stirring at room temperature for 30 minutes. Sodium triacetoxyborohydride (600 mg) was added every 60 minutes 5 times. Thereafter, the mixture was stirred at room temperature for 80 minutes.
  • Trifluoroacetic acid (10 ⁇ L) was added to a solution of 5-(tert-butyl)-6-chloro-1H-indazole-3-amine (18.3 mg) obtained in Production Example 1 and N-(1-acryloylazetidin-3-yl)-2-formyl-1-methyl-1H-imidazole-5-carboxamide (26.0 mg) obtained in Production Example 35 in dichloromethane (2.00 mL), followed by adding sodium triacetoxyborohydride (30 mg). After stirring at room temperature for 1 hour, a saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added to the reaction mixture. The organic layer was separated and washed with saturated saline, followed by drying over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by column chromatography (chloroform:ethanol), thereby obtaining the title compound (25.2 mg) .
  • Example 2 The procedure of Example 2 (steps 4 and 5) was performed except that tert-butyl 3-(2-formyl-1,4-dimethyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate obtained in Production Example 36 was used instead of tert-butyl 3-(2-formyl-4-methylthiazole-5-carboxamide)azetidine-1-carboxylate used in Example 2 (step 4), thereby obtaining the title compound (45.8 mg) .
  • Example 4 The procedure of Example 4 (steps 1 and 2) was performed except that ethyl 3-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-methyl-1H-pyrazole-5-carboxylate (12.6 mg) obtained in Production Example 42 was used instead of methyl 2-(1-((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)ethyl)-1-methyl-1H-imidazole-5-carboxylate used in Example 4 (step 1), thereby obtaining the title compound (7.7 mg) .
  • Example 2 The procedure of Example 2 (steps 1 to 5) was performed except that 2-bromothiazole-5-carboxylic acid was used instead of 2-bromo-4-methylthiazole-5-carboxylic acid used in Example 2 (step 1), thereby obtaining the title compound (4.90 mg).
  • Example 4 The procedure of Example 4 (step 2) was performed except that 3-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1,4-dimethyl-1H-pyrazole-5-carboxylic acid obtained in Production Example 43 was used instead of 2-[1-[(5-tert-butyl-6-chloro-1H-indazol-3-yl)amino]ethyl]-3-methylimidazole-4-carboxylic acid used in Example 4 (step 2), thereby obtaining the title compound (1.29 mg).
  • Example 2 The procedure of Example 2 (steps 4 and 5) was performed except that tert-butyl 3-(2-formyl-1-isopropyl-4-methyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate (91.0 mg) obtained in Production Example 37 was used instead of tert-butyl 3-(2-formyl-4-methylthiazole-5-carboxamide)azetidine-1-carboxylate used in Example 2 (step 4), thereby obtaining the title compound (31.0 mg).
  • Example 21 The procedure of Example 21 (steps 4 to 6) was performed except that 2-(hydroxymethyl)-4-methyl-1-(2,2,2-trifluoroethyl)-1H-imidazole-5-carboxylic acid (162 mg) obtained in Production Example 22 was used instead of 1-(difluoromethyl)-2-(hydroxymethyl)-4-methyl-1H-imidazole-5-carboxylic acid used in Example 21 (step 4), thereby obtaining the title compound (25.7 mg) .
  • Example 2 The procedure of Example 2 (steps 4 and 5) was performed except that tert-butyl 3-(4-ethyl-2-formyl-1-methyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate (55.4 mg) obtained in Production Example 40 was used instead of tert-butyl 3-(2-formyl-4-methylthiazole-5-carboxamide)azetidine-1-carboxylate used in Example 2 (step 4), thereby obtaining the title compound (30.5 mg).
  • Example 2 The procedure of Example 2 (step 5) was performed except that tert-butyl 3-(2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-(difluoromethyl)-1-isopropyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate (1.48 g) obtained in Production Example 50 was used instead of tert-butyl 3-(2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-methylthiazole-5-carboxamide)aminoazetidine-1-carboxylate used in Example 2 (step 5), thereby obtaining the title compound (503 mg) .
  • Example 2 The procedure of Example 2 (steps 4 and 5) was performed except that tert-butyl 3-(4-chloro-2-formyl-1-isopropyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate (111 mg) obtained in Production Example 38 was used instead of tert-butyl 3-(2-formyl-4-methylthiazole-5-carboxamide)azetidine-1-carboxylate used in Example 2 (step 4), thereby obtaining the title compound (64 mg).
  • Example 1 The procedure of Example 1 was performed except that 6-chloro-5-methyl-1H-indazole-3-amine obtained in Production Example 5 was used instead of 5-(tert-butyl)-6-chloro-1H-indazole-3-amine used in Example 1, thereby obtaining the title compound (15.9 mg).
  • Example 1 The procedure of Example 1 was performed except that 6-chloro-5-vinyl-1H-indazole-3-amine obtained in Production Example 2 was used instead of 5-(tert-butyl)-6-chloro-1H-indazole-3-amine used in Example 1, thereby obtaining the title compound (14.8 mg) .
  • Example 1 The procedure of Example 1 was performed except that 6-chloro-5-ethyl-1H-indazole-3-amine obtained in Production Example 3 was used instead of 5-(tert-butyl)-6-chloro-1H-indazole-3-amine used in Example 1, thereby obtaining the title compound (35.2 mg) .
  • Example 1 The procedure of Example 1 was performed except that 5-(tert-butyl)-6-chloro-1H-pyrazolo[4,3-b]pyridine-3-amine obtained in Production Example 4 was used instead of 5-(tert-butyl)-6-chloro-1H-indazole-3-amine used in Example 1, thereby obtaining the title compound (21.4 mg).
  • Example 2 The procedure of Example 2 (steps 4 and 5) was performed except that 5-(tert-butyl)-6-methyl-1H-indazole-3-amine obtained in Production Example 6 was used instead of 5-(tert-butyl)-6-chloro-1H-indazole-3-amine used in Example 2 (step 4), and that tert-butyl 3-(2-formyl-1,4-dimethyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate obtained in Production Example 36 was used instead of tert-butyl 3-(2-formyl-4-methylthiazole-5-carboxamide)azetidine-1-carboxylate used in Example 2 (step 4), thereby obtaining the title compound (18.6 mg) .
  • Example 2 The procedure of Example 2 (steps 4 and 5) was performed except that 5-(tert-butyl)-1H-indazole-3-amine obtained in Production Example 7 was used instead of 5-(tert-butyl)-6-chloro-1H-indazole-3-amine used in Example 2 (step 4), and that tert-butyl 3-(2-formyl-1-isopropyl-4-methyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate obtained in Production Example 37 was used instead of tert-butyl 3-(2-formyl-4-methylthiazole-5-carboxamide)azetidine-1-carboxylate used in Example 2 (step 4), thereby obtaining the title compound (29.1 mg) .
  • Example 2 The procedure of Example 2 (steps 4 and 5) was performed except that 6-chloro-5-(3,3,3-trifluoroprop-1-en-2-yl)-1H-indazole-3-amine obtained in Production Example 8 was used instead of 5-(tert-butyl)-6-chloro-1H-indazole-3-amine used in Example 2 (step 4), and that tert-butyl 3-(4-chloro-2-formyl-1-isopropyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate obtained in Production Example 38 was used instead of tert-butyl 3-(2-formyl-4-methylthiazole-5-carboxamide)azetidine-1-carboxylate used in Example 2 (step 4), thereby obtaining the title compound (8.0 mg).
  • Example 2 The procedure of Example 2 (steps 4 and 5) was performed except that 6-chloro-5-(1-(trifluoromethyl)cyclopropyl)-1H-indazole-3-amine obtained in Production Example 9 was used instead of 5-(tert-butyl)-6-chloro-1H-indazole-3-amine used in Example 2 (step 4), and that tert-butyl 3-(4-chloro-2-formyl-1-isopropyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate obtained in Production Example 38 was used instead of tert-butyl 3-(2-formyl-4-methylthiazole-5-carboxamide)azetidine-1-carboxylate used in Example 2 (step 4), thereby obtaining the title compound (10.0 mg) .
  • Example 2 The procedure of Example 2 (steps 4 and 5) was performed except that 6-chloro-5-isopropyl-1H-indazole-3-amine obtained in Production Example 10 was used instead of 5-(tert-butyl)-6-chloro-1H-indazole-3-amine used in Example 2 (step 4), and that tert-butyl 3-(4-chloro-2-formyl-1-isopropyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate obtained in Production Example 38 was used instead of tert-butyl 3-(2-formyl-4-methylthiazole-5-carboxamide)azetidine-1-carboxylate used in Example 2 (step 4), thereby obtaining the title compound (23.3 mg) .
  • Example 46 The procedure of Example 46 (step 1) was performed except that 1-(4-aminopiperidin-1-yl)prop-2-en-1-one hydrochloride (9.7 mg) was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1), thereby obtaining the title compound (21.4 mg).
  • Example 46 The procedure of Example 46 (steps 1 and 2) was performed except that tert-butyl 3-(methylamino)azetidine-1-carboxylate (9.5 mg) was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1), thereby obtaining the title compound (15.0 mg).
  • Example 46 The procedure of Example 46 (steps 1 and 2) was performed except that tert-butyl piperazine-1-carboxylate (17.3 mg) was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1), thereby obtaining the title compound (16.4 mg).
  • Example 46 The procedure of Example 46 (steps 1 and 2) was performed except that tert-butyl N-(azetidin-3-yl)-N-methyl carbamate hydrochloride (23.7 mg) was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1), thereby obtaining the title compound (19.9 mg).
  • Example 46 The procedure of Example 46 (steps 1 and 2) was performed except that cis-tert-butyl 3-amino-2-methylazetidine-1-carboxylate (17.3 mg) was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1), thereby obtaining the title compound (18.0 mg).
  • Example 46 The procedure of Example 46 (step 1) was performed except that 1-(4-amino-3,3-difluoropyrrolidin-1-yl)prop-2-en-1-one trifluoroacetate (26.9 mg) obtained in Production Example 28 was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1), thereby obtaining the title compound (7.7 mg).
  • Example 46 The procedure of Example 46 (step 1) was performed except that (R)-1-(7-amino-5-azaspiro[2.4]heptan-5-yl)prop-2-en-1-one trifluoroacetate (38.9 mg) obtained in Production Example 29 was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1), thereby obtaining the title compound (22.3 mg).
  • Example 46 The procedure of Example 46 (step 1) was performed except that 1-((3R,4R)-3-amino-4-methylpyrrolidin-1-yl)prop-2-en-1-one trifluoroacetate (37.3 mg) obtained in Production Example 30 was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1), thereby obtaining the title compound (22.2 mg).
  • Example 46 The procedure of Example 46 (steps 1 and 2) was performed except that tert-butyl (3S,4R)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate (18.7 mg) was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1), thereby obtaining the title compound (21.8 mg).
  • Example 46 The procedure of Example 46 (steps 1 and 2) was performed except that tert-butyl (3S,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate (18.9 mg) was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1), thereby obtaining the title compound (24.2 mg).
  • Example 46 The procedure of Example 46 (steps 1 and 2) was performed except that tert-butyl (3R,4R)-3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylate (20.0 mg) was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1), thereby obtaining the title compound (20.2 mg).
  • Example 46 The procedure of Example 46 (steps 1 and 2) was performed except that trans-tert-butyl 3-amino-2-methylazetidine-1-carboxylate (22.6 mg) was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1), thereby obtaining the title compound (16.2 mg).
  • Example 46 The procedure of Example 46 (steps 1 and 2) was performed except that tert-butyl (3R,4S)-3-amino-4-methylpyrrolidine-1-carboxylate (28.2 mg) was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1), thereby obtaining the title compound (16.3 mg).
  • Example 46 The procedure of Example 46 (steps 1 and 2) was performed except that tert-butyl (3S,4R)-3-amino-4-methoxypyrrolidine-1-carboxylate (26.9 mg) was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1), thereby obtaining the title compound (20.7 mg).
  • Example 46 The procedure of Example 46 (steps 1 and 2) was performed except that tert-butyl (3S,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate (18.7 mg) was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1), thereby obtaining the title compound (18.5 mg).
  • Example 46 The procedure of Example 46 (steps 1 and 2) was performed except that tert-butyl (3S,4S)-3-amino-4-methoxypyrrolidine-1-carboxylate (20.0 mg) was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1), and that acrylic anhydride was used instead of acryloyl chloride used in Example 46 (step 2), thereby obtaining the title compound (19.3 mg) .
  • Example 46 The procedure of Example 46 (steps 1 and 2) was performed except that tert-butyl (3S,4S)-3-amino-4-fluoropyrrolidine-1-carboxylate (21.1 mg) was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1), thereby obtaining the title compound (6.1 mg).
  • Example 46 The procedure of Example 46 (steps 1 and 2) was performed except that tert-butyl (3R,4R)-3-amino-4-(cyanomethyl)pyrrolidine-1-carboxylate (20.9 mg) obtained in Production Example 31 was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1), thereby obtaining the title compound (12.9 mg).
  • Example 46 The procedure of Example 46 (steps 1 and 2) was performed except that tert-butyl (3R,4R)-3-amino-4-(fluoromethyl)pyrrolidine-1-carboxylate (17.9 mg) obtained in Production Example 32 was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1), thereby obtaining the title compound (11.3 mg).
  • Example 46 The procedure of Example 46 (steps 1 and 2) was performed except that tert-butyl (3R,4R)-3-amino-4-(methoxymethyl)pyrrolidine-1-carboxylate (16.0 mg) obtained in Production Example 33 was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1), thereby obtaining the title compound (18.5 mg).
  • Example 46 The procedure of Example 46 (steps 1 and 2) was performed except that tert-butyl (3R,4R)-3-amino-4-((dimethylamino)methyl)pyrrolidine-1-carboxylate (10.2 mg) obtained in Production Example 34 was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1), thereby obtaining the title compound (7.9 mg).
  • Example 46 The procedure of Example 46 (steps 1 and 2) was performed except that tert-butyl (3R,4R)-3-amino-4-ethylpyrrolidine-1-carboxylate (8.6 mg) was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1), thereby obtaining the title compound (5.2 mg).
  • Example 46 The procedure of Example 46 (step 1) was performed except that 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-(difluoromethyl)-1-methyl-1H-imidazole-5-carboxylic acid (20 mg) obtained in Production Example 45 was used instead of 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxylic acid used in Example 46 (step 1), and that 1-((3R,4R)-3-amino-4-methylpyrrolidin-1-yl)prop-2-en-1-one trifluoroacetate (39.1 mg) obtained in Production Example 30 was used instead of 3-N-BOC-aminoazetidine used in Example 46 (step 1), thereby obtaining the title compound (20.4 mg).
  • Example 28 The procedure of Example 28 (steps 1 to 3) was performed except that 4-chloro-1-methyl-1H-imidazole-5-carboxylic acid (78.6 mg) obtained in Production Example 13 was used instead of 4-cyano-1-methyl-1H-imidazole-5-carboxylic acid used in Example 28 (step 1), and that (R)-(+)-1-BOC-3-aminopyrrolidine (119 mg) was used instead of 1-Boc-3-aminoazetidine used in Example 28 (step 1), thereby obtaining the title compound (18.0 mg) .
  • Example 70 The procedure of Example 70 (step 1) was performed except that 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-fluoro-1-methyl-1H-imidazole-5-carboxylic acid obtained in Example 72 (step 1) was used instead of 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-(difluoromethyl)-1-methyl-1H-imidazole-5-carboxylic acid used in Example 70 (step 1), and that 1-((3R,4R)-3-amino-4-methylpyrrolidin-1-yl)prop-2-en-1-one trifluoroacetate (37.2 mg) obtained in Production Example 30 was used instead of tert-butyl (3S,4S)-3-amino-4-fluoropyrrolidine-1-carboxylate used in Example 70 (step 1), thereby obtaining
  • Example 70 The procedure of Example 70 (steps 1 and 2) was performed except that 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-fluoro-1-methyl-1H-imidazole-5-carboxylic acid obtained in Example 72 (step 1) was used instead of 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-(difluoromethyl)-1-methyl-1H-imidazole-5-carboxylic acid used in Example 70 (step 1), thereby obtaining the title compound (12 mg).
  • Example 28 The procedure of Example 28 (steps 1 to 3) was performed except that 4-chloro-1-methyl-1H-imidazole-5-carboxylic acid (90.0 mg) obtained in Production Example 13 was used instead of 4-cyano-1-methyl-1H-imidazole-5-carboxylic acid used in Example 28 (step 1), and that tert-butyl (3S,4S)-3-amino-4-fluoropyrrolidine-1-carboxylate (126 mg) was used instead of 1-Boc-3-aminoazetidine used in Example 28 (step 1), thereby obtaining the title compound (13.7 mg).
  • Example 28 The procedure of Example 28 (steps 1 to 3) was performed except that 1-methyl-1H-5-imidazole carboxylic acid (252 mg) was used instead of 4-cyano-1-methyl-1H-imidazole-5-carboxylic acid used in Example 28 (step 1), and that tert-butyl (3R)-3-(methylamino)pyrrolidine-1-carboxylate (450 mg) was used instead of 1-Boc-3-aminoazetidine used in Example 28 (step 1), thereby obtaining the title compound (49.1 mg).
  • Example 70 The procedure of Example 70 (step 1) was performed except that 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1-methyl-1H-imidazole-5-carboxylic acid (35 mg) obtained in Production Example 47 was used instead of 2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-(difluoromethyl)-1-methyl-1H-imidazole-5-carboxylic acid used in Example 70 (step 1), and that 1-((3R,4R)-3-amino-4-methylpyrrolidin-1-yl)prop-2-en-1-one trifluoroacetate (37.2 mg) obtained in Production Example 30 was used instead of tert-butyl (3S,4S)-3-amino-4-fluoropyrrolidine-1-carboxylate used in Example 70 (step 1), thereby
  • Trifluoroacetic acid (1.5 mL) was added to tert-butyl 3-(2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate (12.9 mg) obtained in Production Example 49, followed by stirring at room temperature for 15 minutes. The reaction mixture was concentrated, and toluene was added to the obtained residue, followed by concentrating the residue twice.
  • Trifluoroacetic acid (1.5 mL) was added to tert-butyl 3-(2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1-isopropyl-4-methyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate (165 mg) obtained in Production Example 48, followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated, and toluene was added to the obtained residue, followed by concentrating the residue twice.
  • Trifluoroacetic acid (1.5 mL) was added to tert-butyl 3-(2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1-isopropyl-4-methyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate (47.6 mg) obtained in Production Example 48, followed by stirring at room temperature for 15 minutes. The reaction mixture was concentrated, and toluene was added to the obtained residue, followed by concentrating the residue twice.
  • Example 82 The procedure of Example 82 was performed except that CIS-3-chloroacrylic acid (14.8 mg) was used instead of 2-butynoic acid used in Example 82, thereby obtaining the title compound (10.0 mg).
  • Example 80 The procedure of Example 80 was performed except that tert-butyl 3-(2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-(difluoromethyl)-1-isopropyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate (29.9 mg) obtained in Production Example 50 was used instead of tert-butyl 3-(2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate used in Example 80, thereby obtaining the title compound (16.4 mg).
  • Example 82 The procedure of Example 82 was performed except that (E)-4-methoxybut-2-enoic acid (17.6 mg) was used instead of 2-butynoic acid used in Example 82, thereby obtaining the title compound (1.4 mg).
  • Example 81 The procedure of Example 81 was performed except that ethene sulfonyl chloride (3.64 ⁇ L) was used instead of crotonoyl chloride used in Example 81, thereby obtaining the title compound (3.2 mg).
  • Example 88 steps 1 to 3
  • Example 87 steps 4 to 6
  • 2-methoxyethanol 227 mg
  • 3,5-dimethoxybenzyl alcohol used in Example 88 (step 1)
  • Example 91 The procedure of Example 91 (step 9) was performed except that acetaldehyde (20 mg) was used instead of the formaldehyde solution used in Example 91 (step 9), thereby obtaining the title compound (3.12 mg).
  • Example 91 The procedure of Example 91 (step 9) was performed except that acetone (20 mg) was used instead of the formaldehyde solution used in Example 91 (step 9). After purification by preparative reversed-phase HPLC (water:acetonitrile (0.1% formic acid)), the solvent was concentrated, thereby obtaining the title compound (8.33 mg).
  • Example 91 The procedure of Example 91 (steps 1 to 9) was performed except that N-(tert-butoxycarbonyl)-DL-prolinol was used instead of 1-(tert-butoxycarbonyl)-3-pyrrolidinol used in Example 91 (step 1), and that acetone (20 mg) was used instead of the formaldehyde solution used in Example 91 (step 9), thereby obtaining the title compound (3.5 mg).
  • Example 98 The procedure of Example 98 (steps 1 to 5) was performed except that 2,2-difluoroethanol was used instead of 3-cyclopenten-1-ol used in Example 98 (step 1), thereby obtaining the title compound (72 mg).
  • Example 98 The procedure of Example 98 (steps 1 to 5) was performed except that tetrahydro-4H-pyran-4-ol was used instead of 3-cyclopenten-1-ol used in Example 98 (step 1), thereby obtaining the title compound (25.3 mg).
  • Example 98 The procedure of Example 98 (steps 1 to 5) was performed except that (S)-(+)-3-hydroxytetrahydrofuran was used instead of 3-cyclopenten-1-ol used in Example 98 (step 1), thereby obtaining the title compound (54.1 mg).
  • Example 98 The procedure of Example 98 (steps 1 to 5) was performed except that tetrahydro-2H-pyran-3-ol was used instead of 3-cyclopenten-1-ol used in Example 98 (step 1), thereby obtaining the title compound (18.5 mg).
  • Example 98 The procedure of Example 98 (steps 1 to 5) was performed except that cyclopentanol was used instead of 3-cyclopenten-1-ol used in Example 98 (step 1), thereby obtaining the title compound (100 mg).
  • Trifluoroacetic acid (1.0 mL) was added to tert-butyl 3-(5-((1-acryloylazetidin-3-yl)carbamoyl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-chloro-1H-imidazol-1-yl)azetidine-1-carboxylate (30 mg) obtained in Example 106 (step 2). The mixture was stirred and concentrated, followed by adding THF (1.0 mL), N,N-diisopropylethylamine (56 ⁇ L), and acetic anhydride (5 ⁇ L) to the obtained residue.
  • THF 1.0 mL
  • N,N-diisopropylethylamine 56 ⁇ L
  • acetic anhydride (5 ⁇ L)
  • Example 98 The procedure of Example 98 (steps 1 to 5) was performed except that cyclohexanol was used instead of 3-cyclopenten-1-ol used in Example 98 (step 1), thereby obtaining the title compound (20.5 mg).
  • Example 97 The procedure of Example 97 (steps 1 to 4) was performed except that cyclopentylmethanol was used instead of (R)-(-)-3-hydroxytetrahydrofuran used in Example 97 (step 1), thereby obtaining the title compound (140 mg).
  • Example 98 The procedure of Example 98 (steps 1 to 5) was performed except that (-)-menthol was used instead of 3-cyclopenten-1-ol used in Example 98 (step 1), thereby obtaining the title compound (10.7 mg).
  • Example 97 The procedure of Example 97 (steps 1 to 4) was performed except that 4-methoxycyclohexanol was used instead of (R)-(-)-3-hydroxytetrahydrofuran used in Example 97 (step 1), thereby obtaining the title compound (140 mg).
  • Example 91 step 9
  • 2-(((1-acetyl-5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-N-(1-acryloylazetidin-3-yl)-4-chloro-1-(piperidin-3-yl)-1H-imidazole-5-carboxamide trifluoroacetate (20 mg) obtained in Example 117 (step 2) was used instead of N-(1-acryloylazetidin-3-yl)-2-(((5-(tert-butyl)-6-chloro-1H-indazol-3-yl)amino)methyl)-4-(difluoromethyl)-1-(pyrrolidin-3-yl)-1H-imidazole-5-carboxamide formate used in Example 91 (step 9), thereby obtaining the title compound (8.05 mg).
  • Example 113 The procedure of Example 113 (steps 1 and 2) was performed except that oxetane-3-one (11.5 mg) was used instead of difluoroacetaldehyde ethyl hemiacetal used in Example 113 (step 1), thereby obtaining the title compound (29.4 mg).
  • Example 122 The procedure of Example 122 (steps 1 and 2) was performed except that allyl bromide was used instead of benzyl bromide used in Example 122 (step 1), thereby obtaining the title compound (135 mg).
  • Example 125 The procedure of Example 125 (steps 1 to 3) was performed except that tert-butyl (2R,4S)-4-hydroxy-2-methyl-pyrrolidine-1-carboxylate (501 mg) was used instead of tert-butyl (2S,3S)-3-hydroxy-2-methyl-pyrrolidine-1-carboxylate used in Example 125 (step 1), thereby obtaining the title compound (71.8 mg).
  • Example 1 The procedure of Example 1 was performed except that 5-bromo-6-chloro-1H-indazole-3-amine obtained in Production Example 5 (step 1) was used instead of 5-(tert-butyl)-6-chloro-1H-indazole-3-amine used in Example 1, thereby obtaining the title compound (4.9 mg).
  • Example 2 The procedure of Example 2 (steps 4 and 5) was performed except that tert-butyl 3-(2-formyl-1-methyl-4-phenyl-1H-imidazole-5-carboxamide)azetidine-1-carboxylate (84 mg) obtained in Production Example 39 was used instead of tert-butyl 3-(2-formyl-4-methylthiazole-5-carboxamide)azetidine-1-carboxylate used in Example 2 (step 4), thereby obtaining the title compound (66.0 mg).
  • the following is a list of the compounds of Examples 1 to 126 and Reference Examples 1 to 3.
  • Test Example 1 A test of compounds on whether to bind to KRASG12C
  • Test compounds were prepared in the form of a 10 mM DMSO solution.
  • K-Ras4B (1-169) and G12C K-Ras4B (1-169) proteins were mixed and diluted with a buffer (1 ⁇ TBS, 0.1mM TCEP) to prepare individual 1 ⁇ M protein solutions.
  • a 10 mM test compound was diluted tenfold with DMSO to make a 1 mM solution, and then diluted fivefold with DMSO to make a 200 ⁇ M solution. The 200 ⁇ M solution was further diluted fivefold to make a 40 ⁇ M solution.
  • the final compound concentration was 10 ⁇ M, 1 ⁇ L of a 200 ⁇ M test compound was added to 19 ⁇ L of a 1 ⁇ M protein solution.
  • a spectrum of a polyvalent ion was collectively converted to a molecular weight by using OpenLynx software by the MaxEnt technique, and a compound binding rate was obtained from the ratio of a signal intensity that corresponds to the molecular weight of a protein to a signal intensity that corresponds to the molecular weight of a compound binding to the protein.
  • test compounds were measured at their final compound concentration of 2 ⁇ M.
  • a binding rate of 80% or more is rated “A”
  • a binding rate of 60% or more and less than 80% is rated “B”
  • a binding rate of 40% or more and less than 60% is rated “C”
  • a binding rate of 20% or more and less than 40% is rated “D”
  • a binding rate of less than 20% is rated “E.”
  • the following table shows the results. Almost no compounds of the present invention binded to K-Ras4B (1-169).
  • the "binding rate” (%) for each of K-Ras4B (1-169) and G12C K-Ras4B (1-169) refers to the ratio of the signal intensity of binded forms to the sum of the singal intensity of non-binded forms and the singal intensity of binded forms.
  • Test Example 2 Evaluation of inhibitory activity of compounds on KRAS G12C nucleotide (GDP-GTP) exchange reaction
  • KRAS G12C For the preparation of KRAS G12C to which Bodipy FL GDP was bound, first, 50 ⁇ M KRAS G12C (amino acid region: 1-169) and 1 mM Bodipy FL GDP (Invitrogen, G22360) were incubated for 1 hour in a buffer (20 mM Tris-HCl (pH 7.5), 50 mM NaCl, 1 mM DTT) in ice in the presence of 2.5 mM EDTA. Thereafter, MgCl 2 with a final concentration of 10 mM was added, and the mixture was incubated at room temperature for 30 minutes. The protein was allowed to pass through a NAP-5 column to remove free nucleotides and was used for compound evaluation.
  • a buffer (20 mM Tris-HCl (pH 7.5), 50 mM NaCl, 1 mM DTT) in ice in the presence of 2.5 mM EDTA.
  • MgCl 2 with a final concentration of 10 mM
  • the compound of the present invention was diluted stepwise with dimethyl sulfoxide (DMSO). Subsequently, a solution of the gradually diluted compound of the present invention in DMSO (the final concentration of DMSO: 5%) and KRAS G12C (25 nM) bound to Bodipy FL GDP were added to a reaction buffer (20 mM Tris-HCl (pH 7.5), 100 mM NaCl, 1 mM MgCl 2 , 2 mM DTT, 0.1% Tween20), followed by preincubation at 25°C for 4 hours.
  • DMSO dimethyl sulfoxide
  • Example IC50 (nM) Example IC50 (nM)
  • Example IC50 (nM) Example IC50 (nM) 1 16 34 13 67 24 100 14 2 365 35 8 68 99 101 7 3 9 36 19 69 6650 102 5 4 1560 37 5479 70 79 103 5 5 10 38 2168 71 117 104 9 6 791 39 870 72 71 105 8 7 4257 40 27 73 52 106 8 783 41 14 74 36 107 4 9 3143 42 68 75 16 108 9 10 129 43 809 76 13 109 23 11 1064 44 180 77 142 110 9 12 16 45 24 78 20 111 15 13 15 46 92 79 122 112 5 14 24 47 1729 80 63 113 5 15 84 48 126 81 2634 114 7 16 25 49 208 82 209 115 7 17 17 50 4276 83 2347 116
  • Test Example 3 A measurement test of growth inhibition activity on KRAS-G12C mutant cell line (NCI-H358) (in vitro)
  • NCI-H358 cells (ATCC, Cat#: CRL-5807), which are a KRAS-G12C mutant human lung cancer cell line, were suspended in a 10% fetal bovine serum-containing RPMI1640 medium (manufactured by Fujifilm Wako Pure Chemical Corporation.). The cell suspension was seeded into each well of a 384-well flat-bottom microplate and cultured in an incubator containing 5% CO 2 gas at 37°C for 1 day. The test compound was dissolved in DMSO, and diluted with DMSO to give a concentration 500 times the final concentration.
  • the solution of the test compound in DMSO was diluted with the medium used for suspending cells and added to each well of the cell-culture plate to give a DMSO final concentration of 0.2%, followed by culture in an incubator containing 5% CO 2 gas at 37°C for another 3 days.
  • the cell count after 3-day culture in the presence of the compound was measured using CellTiter-Glo2.0 (manufactured by Promega Corporation) in accordance with the protocol recommended by Promega Corporation.
  • the growth inhibition rate was calculated from the following equation, and the concentration of the test compound at which 50% inhibition was achieved (IC50 (nM)) was determined.
  • IC50 (nM) concentration of the test compound at which 50% inhibition was achieved
  • Example IC50 (nM) Example IC50 (nM)
  • Example IC50 (nM) Example IC50 (nM)
  • Example IC50 (nM) 3 114 76 232 104 91 115 56 13 135 78 350 105 76 123 21 29 34 93 40 106 42 124 19 33 153 97 52 107 78 126 35 35 67 101 54 112 52
  • Reference Example 1 >10000 64 241 102 69 113 22 75 142 103 29 114 32

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WO2021215544A1 (fr) * 2020-04-24 2021-10-28 Taiho Pharmaceutical Co., Ltd. Inhibiteurs de protéine kras g12d
CN115260103A (zh) * 2022-09-19 2022-11-01 苏州美诺医药科技有限公司 一种4,5-二卤代-1-(二氟甲基)-1h-咪唑的制备方法
US11697657B2 (en) 2019-10-28 2023-07-11 Merck Sharp & Dohme Llc Small molecule inhibitors of KRAS G12C mutant

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US20230181536A1 (en) * 2020-04-24 2023-06-15 Taiho Pharmaceutical Co., Ltd. Anticancer combination therapy with n-(1-acryloyl-azetidin-3-yl)-2-((1h-indazol-3-yl)amino)methyl)-1h-imidazole-5-carboxamide inhibitor of kras-g12c
BR112022022861A2 (pt) * 2020-05-13 2022-12-20 Basf Se Compostos, composições agrícolas, semente e métodos para combater ou controlar pragas invertebradas, proteger plantas em crescimento e tratar ou proteger um animal
EP3909950A1 (fr) * 2020-05-13 2021-11-17 Basf Se Composés hétérocycliques destinés à la lutte contre les organismes nuisibles invertébrés
CN111943879A (zh) * 2020-08-03 2020-11-17 南通大学 一种（3s，4r）3-氨基-4（甲氧基甲基）吡咯烷-1-甲酸叔丁酯及其合成方法
WO2023031781A1 (fr) 2021-09-01 2023-03-09 Novartis Ag Combinaisons pharmaceutiques comprenant un inhibiteur de tead et leurs utilisations pour le traitement de cancers
WO2024040131A1 (fr) 2022-08-17 2024-02-22 Treeline Biosciences, Inc. Inhibiteurs de pyridopyrimidine kras
WO2024112654A1 (fr) 2022-11-21 2024-05-30 Treeline Biosciences, Inc. Inhibiteurs de kras spirocycliques de dihydropyranopyrimidine

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JP2014111559A (ja) * 2012-07-04 2014-06-19 Nissan Chem Ind Ltd ピラゾール誘導体および有害生物防除剤
WO2014152588A1 (fr) 2013-03-15 2014-09-25 Araxes Pharma Llc Inhibiteurs covalents de k-ras g12c
CA2926328C (fr) 2013-10-10 2022-11-29 Araxes Pharma Llc Quinazoline substituee et derives de quinoline et compositions pharmaceutiques connexes utiles comme inhibiteurs de kras g12c
AR102094A1 (es) * 2014-09-25 2017-02-01 Araxes Pharma Llc Inhibidores de proteínas kras con una mutación g12c
CA3042929A1 (fr) * 2016-11-08 2018-05-17 Cancer Research Technology Limited Derives de pyrimidinone en tant qu'inhibiteurs de cdc7
JOP20190186A1 (ar) 2017-02-02 2019-08-01 Astellas Pharma Inc مركب كينازولين
CN109670389B (zh) 2017-10-16 2023-04-07 富士通株式会社 评价人脸图像中的光照条件的方法和设备
JP6648797B2 (ja) 2018-10-04 2020-02-14 株式会社三洋物産 遊技機

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11697657B2 (en) 2019-10-28 2023-07-11 Merck Sharp & Dohme Llc Small molecule inhibitors of KRAS G12C mutant
WO2021215544A1 (fr) * 2020-04-24 2021-10-28 Taiho Pharmaceutical Co., Ltd. Inhibiteurs de protéine kras g12d
CN115260103A (zh) * 2022-09-19 2022-11-01 苏州美诺医药科技有限公司 一种4,5-二卤代-1-(二氟甲基)-1h-咪唑的制备方法

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